Glycyrrhetinic acid derivatives for treating hyperkalemia

ABSTRACT

The present invention provides a compound of formula (I) or a salt thereof:wherein X, L, V, R1, R2, R3 and R4, are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. 119(e)to U.S. provisional application 62/541,095 filed on 4 Aug. 2017, theentire contents of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit 11β-HSD2 andmethods of using these compounds to remove potassium from thegastrointestinal tract, including methods of treating hyperkalemia.

BACKGROUND OF THE INVENTION

Potassium is the most abundant cation in the intracellular fluid andplays an important role in normal human physiology, especially withregard to the firing of action potential in nerve and muscle cells.Total body potassium content is about 50 mmol/kg of body weight, whichtranslates to approximately 3500 mmols of potassium in a 70 kg adult.The bulk of total body potassium is intracellular (˜98%), with onlyapproximately 70 mmol (˜2%) in the extracellular space. This largedifferential between intracellular potassium (˜120-140 mmol/L) andextracellular potassium (˜4 mmol/L) largely determines the restingmembrane potential of cells.

As a consequence, very small absolute changes in the extracellularpotassium concentration will have a major effect on this ratio andconsequently on the function of excitable tissues (muscle and nerve).Extracellular potassium levels are therefore tightly regulated.

Two separate and cooperative systems participate in potassiumhomeostasis, one regulating external potassium balance (the body parityof potassium intake vs. potassium elimination) while the other regulatesinternal potassium balance (distribution between intracellular andextracellular fluid compartments. Intracellular/extracellular balanceprovides short-term management of changes in serum potassium, and isprimarily driven physiologically by the action of Na⁺, K⁺-ATPase“pumps,” which use the energy of ATP hydrolysis to pump Na⁺ and K⁺against their concentration gradients. Almost all cells possess a Na⁺,K⁺-ATPase. Body parity is managed by elimination mechanisms via thekidney and gastrointestinal tract: in healthy kidneys, 90-95% of thedaily potassium load is excreted through the kidneys with the balanceeliminated in the feces.

Due to the fact that intracellular/extracellular potassium ratio(K_(i):K_(e) ratio) is the major determinant of the resting membranepotential of cells, small changes in K_(e) (i.e., serum [K]) haveprofound effects on the function of electrically active tissues, such asmuscle and nerve. Potassium and sodium ions drive action potentials innerve and muscle cells by actively crossing the cell membrane andshifting the membrane potential, which is the difference in electricalpotential between the exterior and interior of the cell. In addition toactive transport, K⁺ can also move passively between the extracellularand intracellular compartments. An overload of passive K⁺ transport,caused by higher levels of blood potassium, depolarizes the membrane inthe absence of a stimulus. Excess serum potassium, known ashyperkalemia, can disrupt the membrane potential in cardiac cells thatregulate ventricular conduction and contraction. Clinically, the effectsof hyperkalemia on cardiac electrophysiology are of greatest concernbecause they can cause arrhythmias and death. Since the bulk of bodyparity is maintained by renal excretion, it is therefore to be expectedthat as kidney function declines, the ability to manage total bodypotassium becomes impaired.

Hyperkalemia is defined as a serum potassium level above the normalrange, typically >5.0 mmol/L. Moderate hyperkalemia (serum potassiumabove 6.0 mEq/L) has been reported to have a 1-day mortality rate up to30 times higher than that of patients with serum potassium less than 5.5mEq/L. Severe hyperkalemia (serum K+ of at least 6.5 mmol/L) is apotentially life-threatening electrolyte disorder that has been reportedto occur in 1% to 10% of all hospitalized patients and constitutes amedical emergency requiring immediate treatment. Hyperkalemia is causedby deficiencies in potassium excretion, and since the kidney is theprimary mechanism of potassium removal, hyperkalemia commonly affectspatients with kidney diseases such as chronic kidney disease (CKD) orend-stage renal disease (ESRD). However, episodes of hyperkalemia canoccur in patients with normal kidney function, where it is still alife-threatening condition. For example, in hospitalized patients,hyperkalemia has been associated with increased mortality in patientsboth with and without CKD. While CKD is the most common predisposingcondition for hyperkalemia, the mechanisms driving hyperkalemiatypically involve a combination of factors, such as increased dietarypotassium intake, disordered distribution of potassium betweenintracellular and extracellular compartments and abnormalities inpotassium excretion. These mechanisms can be modulated by a variety offactors with causality outside of CKD. These include the presence ofother comorbidities, such as type 2 diabetes mellitus (T2DM),cardiovascular disease (CVD) or the use of co-medications that candisrupt potassium homeostasis as side effects, such as blockade of therenin-angiotensin-aldosterone system (RAAS), for example, withangiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptorblockers (ARBs).

Serum potassium can be lowered by two general mechanisms: the first isby shifting potassium intracellularly using agents such as insulin,albuterol or sodium bicarbonate. The second is by excreting it from thebody using 1 of 4 routes: the stool with K binding resins such as sodiumpolystyrene sulfonate (Na PSS), the urine with diuretics, the blood withhemodialysis or the peritoneal fluid with peritoneal dialysis. Otherthan Na PSS, the medications that treat hyperkalemia, such as insulin,diuretics, beta agonists and sodium bicarbonate, simply causehypokalemia as a side effect and are not suitable as chronic treatments.Definitive therapy necessitates the removal of potassium from the body.Studies have confirmed that reducing serum potassium levels inhyperkalemia patients actually reduces the mortality risk, furthersolidifying the role of excess potassium in the risk of death. While NaPSS is the current standard of care treatment for potassium reduction inthe U.S., the calcium salt of PSS (Ca PSS) is also commonly used inother parts of the world, including Europe (e.g., Resonium) and Japan.Kayexalate/Na PSS is poorly tolerated causing a high incidence of GIside effects including nausea, vomiting, constipation and diarrhea. Inaddition, Kayexalate is a milled product and consists of irregularlyshaped particles ranging in size from about 1-150 μm in size, and hassand-like properties in the human mouth: on ingestion, it gives a strongsensation of foreign matter on the palate and this sensation contributesnegatively to patient compliance. In total, the physical properties andassociated side-effects of Kayexalate lead to poor compliance and renderthe drug suboptimal for chronic use. Due to these properties, there hasbeen a long felt need to provide an optimal drug for chronic use.

The mineralocorticoid receptor (or MR, MLR, MCR), also known as thealdosterone receptor or nuclear receptor subfamily 3, group C, member 2,(NR3C2) is a protein that in humans is encoded by the NR3C2 gene that islocated on chromosome 4q31.1-31.2. MR is a receptor with equal affinityfor mineralocorticoids and glucocorticoids including cortisol. Itbelongs to the nuclear receptor family where the ligand diffuses intocells, interacts with the receptor and results in a signal transductionaffecting specific gene expression in the nucleus. MR is expressed inmany tissues, such as the kidney, colon, heart, central nervous system(hippocampus), brown adipose tissue and sweat glands. Activation of themineralocorticoid receptor by ligands aldosterone and cortisol inepithelial tissues promotes excretion of potassium. In intact animals,the MR is “protected” from the greater concentration of cortisol(100-1000 fold) by co-localization of an enzyme, 11β-hydroxysteroiddehydrogenase 2; (referred to herein as HSD2), that oxidizes cortisol tothe inactive metabolite cortisone. HSD2, thus prevents MR activation andtherefore inhibits excretion of potassium.

Accordingly, inhibition of HSD2 to prevent inactivation of cortisolactivation of the MR is a promising mechanism for promoting potassiumexcretion, for example, in the treatment of hyperkalemia.

SUMMARY OF THE INVENTION

In one aspect of the present invention there is provided a compound offormula I or a salt thereof:

wherein,

-   -   X is a bond, —O—, —C(O)—, —N(R_(x))—, —C(O)N(R_(x))—,        —N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—;    -   V is —C(O)O—, —C(O)N(R₅)—, —C(O)N(R₅)O—, —NH—C(O)—N(R₅)— or        NH—S(O)_(n)—;    -   L is a bond, alkylene wherein one or more non-adjacent methylene        groups of said alkylene are replaced with —O—; divalent aryl or        divalent heteroaryl; or L is alkylene-Y-alkylene wherein Y is O,        NR_(x), S, SO, SO₂ or a divalent heterocycle; wherein said        alkylene groups are optionally substituted with OH, —C(O)O—R₁,        alkyl or alkyl substituted with OH or —C(O)O—R₁; and wherein a        carbon of said alkylene groups and R_(x) optionally together        form a heterocycle; provided that when X is other than a bond,        then L is other than a bond;    -   R₁ is alkyl optionally substituted with halogen, OH, amino, oxo,        carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy,        alkoxycarbonyloxy, aminocarbonyl, a carbocycle optionally        substituted with alkyl, haloalkyl, oxo, amino and halogen and a        heterocycle optionally substituted with alkyl, oxo, amino and        halogen; and a carbocycle or heterocycle optionally substituted        with alkyl, haloalkyl, oxo, amino and halogen; wherein one or        more non-adjacent methylene groups in any of the foregoing alkyl        groups is replaced with O;    -   R₂ is H or R₁;    -   R₃ is absent, Me; provided that when —X-L-C(O)O—R₁ depends from        the carbon to which R₃ depends then R₃ is absent; or R₃ is        —Z-L-C(O)O—R₁ wherein Z is a bond, —O—, —N(R_(x))—,        —C(O)N(R_(x))—, —N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or        —N(R_(x))—S(O)_(n)—; and    -   R₄ is absent, H or OH; provided that when —X-L-C(O)O—R₁ depends        from the carbon to which R₄ depends then R₄ is H or absent;    -   R₅ is H or alkyl;    -   R_(x) is H, —C(O)O—R₁, or alkyl optionally substituted with        —C(O)O—R₁; and    -   n is 1 or 2.

In another aspect of the invention, there are provided compositionscomprising compounds of Formula I and a carrier, diluent or excipient.

In another aspect of the invention, there is provided a method ofinhibiting conversion of cortisol to cortisone by HSD2 comprisingcontacting HSD2 with a compound of Formula I.

In another aspect of the invention, there is provided a method forpromoting activation MR in a mammal, comprising administering to saidmammal an effective amount of a compound of Formula I.

In another aspect of the invention, there is provided a method ofreducing potassium levels in plasma of a mammal, comprisingadministering to said mammal an effective amount of a compound ofFormula I.

In another aspect of the invention, there is provided a method forpromoting potassium ion secretion into the colonic lumen of a mammal,comprising administering to said mammal an effective amount of acompound of Formula I.

In another aspect of the invention, there is provided a method fortreating hyperkalemia in a mammal, comprising administering to saidmammal an effective amount of a compound of Formula I.

In another aspect of the invention, there is provided a method fortreating or preventing hyperkalemia in a mammal comprisingcoadministering a compound of Formula I with an inhibitor of therenin-angiotensin-aldosterone system (RAAS).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the synergistic effect on potassium excretion infeces upon administration of an HSD2 inhibitor in combination with anNHE3 inhibitor.

FIG. 2 is an illustration of 11-β-hydroxysteroid dehydrogenase 2 (HSD2)inhibition in an epithelial cell allowing cortisol to activate themineralocorticoid receptor (MR) which facilitates excretion of potassiuminto the lumen.

FIG. 3 depicts the structure of glycyrrhetinic acid with the numberingof the carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

Glycyrrhizin (or glycyrrhizic acid or glycyrrhizinic acid) is extract ofthe plant called Glycyrrhiza which is derived from the ancient Greekterm ‘glykos’, meaning sweet, and ‘rhiza’, meaning root. Glycyrrhiza wasindulged upon by many prophets and pharaohs. Licorice extract has beenutilized in the battlefields and the desert where soldiers and travelersdrank it to suppress their thirst sensation on long marches.Glycyrrhetic acid, the active metabolite in licorice, inhibits HSD2 witha resultant cortisol-induced mineralocorticoid effect and the tendencytowards the reduction of potassium levels. While glycyrrhetic acidlowers potassium levels, it is associated with abnormal heart rhythms,hypertension, edema, lethargy, congestive heart failure, hypokalemia andrhabdomyolysis. Accordingly, it would be desirable to provide a compoundthat promotes potassium excretion in patients suffering fromhyperkalemia like glycyrrhetinic acid without the undesirable sideeffects.

The present invention provides a compound of formula I or a saltthereof:

wherein,

-   -   X is a bond, —O—, —C(O)—, —N(R_(x))—, —C(O)N(R_(x))—,        —N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—;    -   V is —C(O)O—, —C(O)N(R₅)—, —C(O)N(R₅)O—, —NH—C(O)—N(R₅)— or        NH—S(O)_(n)—;    -   L is a bond, alkylene wherein one or more non-adjacent methylene        groups of said alkylene are replaced with —O—; divalent aryl or        divalent heteroaryl; or L is alkylene-Y-alkylene wherein Y is O,        NR_(x), S, SO, SO₂ or a divalent heterocycle; wherein said        alkylene groups are optionally substituted with OH, —C(O)O—R₁,        alkyl or alkyl substituted with OH or —C(O)O—R₁; and wherein a        carbon of said alkylene groups and R_(x) optionally together        form a heterocycle; provided that when X is other than a bond,        then L is other than a bond;    -   R₁ is alkyl optionally substituted with halogen, OH, amino, oxo,        carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy,        alkoxycarbonyloxy, aminocarbonyl, a carbocycle optionally        substituted with alkyl, haloalkyl, oxo, amino and halogen and a        heterocycle optionally substituted with alkyl, oxo, amino and        halogen; and a carbocycle or heterocycle optionally substituted        with alkyl, haloalkyl, oxo, amino and halogen; wherein one or        more non-adjacent methylene groups in any of the foregoing alkyl        groups is replaced with O;    -   R₂ is H or R₁;    -   R₃ is absent, Me; provided that when —X-L-C(O)O—R₁ depends from        the carbon to which R₃ depends then R₃ is absent; or R₃ is        —Z-L-C(O)O—R₁ wherein Z is a bond, —O—, —N(R_(x))—,        —C(O)N(R_(x))—, —N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or        —N(R_(x))—S(O)_(n)—; and    -   R₄ is absent, H or OH; provided that when —X-L-C(O)O—R₁ depends        from the carbon to which R₄ depends then R₄ is H or absent;    -   R₅ is H or alkyl;    -   R_(x) is H, —C(O)O—R₁, or alkyl optionally substituted with        —C(O)O—R₁; and    -   n is 1 or 2.

In a particular embodiment, compounds of the invention contain an estermoiety pending from the 3-, 23- and/or 24-position of the fused ringsystem. In an embodiment, following administration to a subject of acompound of the invention, the ester moiety is metabolized in plasma orliver to a less active acid form. In another embodiment, the compound ofthe invention has equal or greater HSD2 inhibitory activity thanglycyrrhetinic acid. In another embodiment, the compound of theinvention has greater HSD2 inhibitory activity than glycyrrhetinic acid.

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl, whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), andheteroaroyl.

“Alkyl” means a branched or unbranched, saturated or unsaturated (i.e.alkenyl, alkynyl) aliphatic hydrocarbon group, having up to 12 carbonatoms unless otherwise specified. When used as part of another term, forexample, “alkylamino”, “cycloalkyl”, “alkylene” etc., the alkyl portionmay be a saturated hydrocarbon chain, however also includes unsaturatedhydrocarbon carbon chains such as “alkenylamino” and “alkynylamino.Examples of particular alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl,2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. Theterms “lower alkyl” “C₁-C₄ alkyl” and “alkyl of 1 to 4 carbon atoms” aresynonymous and used interchangeably to mean methyl, ethyl, 1-propyl,isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-butyl. Unless specified,substituted, alkyl groups may contain, for example, one, two, three orfour substituents, which may be the same or different. Examples ofsubstituents are, unless otherwise defined, halogen, amino, hydroxyl,protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino,guanidino, urea, sulfonyl, sulfinyl, aminosulfonyl, alkylsulfonylamino,arylsulfonylamino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, acarbocycle, and a heterocycle. Examples of the above substituted alkylgroups include, but are not limited to; cyanomethyl, nitromethyl,hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl,carboxymethyl, carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl,allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl,ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl,iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl),2-amino(isopropyl), 2-carbamoyloxyethyl and the like. The alkyl groupmay also be substituted with a carbocycle group. Examples includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, andcyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl,-butyl, -pentyl, -hexyl groups, etc. Substituted alkyls includesubstituted methyls, e.g., a methyl group substituted by the samesubstituents as the “substituted C_(n)-C_(m) alkyl” group. Examples ofthe substituted methyl group include groups such as hydroxymethyl,protected hydroxymethyl (e.g., tetrahydropyranyloxymethyl),acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl,carboxymethyl, bromomethyl and iodomethyl. In an embodiment, alkyl issaturated. In an embodiment, alkyl is unsaturated. In an embodiment,alkyl is partially unsaturated.

“Amidine” means the group —C(NH)—NHR in which R is H, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. A particular amidine is the group—NH—C(NH)—NH₂.

“Amino” means primary (i.e. —NH₂), secondary (i.e. —NRH) and tertiary(i.e. —NRR) amines in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Particular secondary and tertiary amines are alkylamine, dialkylamine,arylamine, diarylamine, aralkylamine and diaralkylamine, wherein thealkyl is as herein defined and optionally substituted. Particularsecondary and tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine,dipropylamine and diisopropylamine.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, imines, as well as many N-heteroatom derivatives which canbe removed to regenerate the desired amine group. Suitableamino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl,t-butyloxycarbonyl (“Boc”), benzyloxycarbonyl (“CBz”) and9-fluorenylmethyleneoxycarbonyl (“Fmoc”). Further examples of thesegroups are found in Wuts. Greene's Protective Groups in OrganicSynthesis. 5th ed. New York: John Wiley & Sons, Inc., 2014. The term“protected amino” refers to an amino group substituted with one of theabove amino-protecting groups.

“Aryl” when used alone or as part of another term means a carbocyclicaromatic group whether or not fused having the number of carbon atomsdesignated or if no number is designated, up to 14 carbon atoms.Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl,naphthacenyl, and the like (see e.g., Dean, J. A., ed. Lange's Handbookof Chemistry. 13th ed. New York: McGraw-Hill, 1985, Table 7-2). Aparticular aryl is phenyl. Substituted phenyl or substituted aryl meansa phenyl group or aryl group substituted with one, two, three, four orfive substituents, for example 1-2, 1-3 or 1-4 substituents chosen,unless otherwise specified, from halogen (F, Cl, Br, I), hydroxy,protected hydroxy, cyano, nitro, alkyl (for example C₁-C₆ alkyl), alkoxy(for example C₁-C₆ alkoxy), benzyloxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl,alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino,arylsulonylaminoalkyl, heterocyclylsulfonylamino,heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groupsspecified. One or more methyne (CH) and/or methylene (CH₂) groups inthese substituents may in turn be substituted with a similar group asthose denoted above. Examples of the term “substituted phenyl” includesbut is not limited to a mono- or di(halo)phenyl group, such as2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, theprotected-hydroxy derivatives thereof and the like; a nitrophenyl groupsuch as 3- or 4-nitrophenyl; a cyanophenyl group, for example,4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl,4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono ordi(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such as 4-carboxyphenyl; a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; a mono- ordi(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl; disubstituted phenyl groups such as3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl,3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl; trisubstituted phenylgroups such as 3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino; and tetrasubstitutedphenyl groups such as 3-methoxy-4-benzyloxy-5-methyl-6-phenylsulfonylamino. Particular substituted phenyl groups include the2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl,3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl,3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Fused aryl rings may also be substituted with any, for example1, 2 or 3, of the substituents specified herein in the same manner assubstituted alkyl groups.

“Carbocyclyl”, “carbocyclic”, “carbocycle” and “carbocyclo” alone andwhen used as a moiety in a complex group such as a carbocycloalkylgroup, refer to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14carbon atoms, for example 3 to 7 carbon atoms or 3 to 6 carbon atoms,which may be saturated or unsaturated, aromatic or non-aromatic.Particular saturated carbocyclic groups are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl groups. A particular saturated carbocycle iscyclopropyl. Another particular saturated carbocycle is cyclohexyl.Particular unsaturated carbocycles are aromatic e.g. aryl groups aspreviously defined, for example phenyl. The terms “substitutedcarbocyclyl”, “carbocycle” and “carbocyclo” mean these groupssubstituted by the same substituents as the “substituted alkyl” group.

“Carboxy-protecting group” as used herein refers to one of the esterderivatives of the carboxylic acid group commonly employed to block orprotect the carboxylic acid group while reactions are carried out onother functional groups on the compound. Examples of such carboxylicacid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl,benzhydryl, 4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl,alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl,4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl,trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule. Inparticular, it is important not to subject a carboxy-protected moleculeto strong nucleophilic bases, such as lithium hydroxide or NaOH, orreductive conditions employing highly activated metal hydrides such asLiAlH₄. Such harsh removal conditions are also to be avoided whenremoving amino-protecting groups and hydroxy-protecting groups,discussed below. Particular carboxylic acid protecting groups are thealkyl (e.g., methyl, ethyl, t-butyl), allyl, benzyl and p-nitrobenzylgroups. Similar carboxy-protecting groups used in the cephalosporin,penicillin and peptide arts can also be used to protect carboxy groupsubstituents. Further examples of these groups are found in Greene, T.W., and P. G. M. Wuts. Protective Groups in Organic Synthesis. 2nd ed.New York: John Wiley & Sons, Inc. 1991, Chapter 5; Haslam, E. ProtectiveGroups in Organic Chemistry. New York: Plenum Press 1973, Chapter 5; andGreene, T. W. Protective Groups in Organic Synthesis. New York: JohnWiley & Sons, Inc. 1981, Chapter 5. The term “protected carboxy” refersto a carboxy group substituted with one of the above carboxy-protectinggroups.

“Alkoxycarbonyl” means the group —C(═O)OR in which R is alkyl. Aparticular group is C₁-C₆ alkoxycarbonyl, wherein the R group is C₁-C₆alkyl.

“Guanidine” means the group —NH—C(NH)—NHR in which R is hydrogen, alkyl,a carbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. A particular guanidine is the group—NH—C(NH)—NH₂.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g., TBS, TBDPS) groups. Further examples of these groupsare found in Greene, T. W., and P. G. M. Wuts. Protective Groups inOrganic Synthesis. 2nd ed. New York: John Wiley & Sons, Inc. 1991,Chapters 2-3; Haslam, E. Protective Groups in Organic Chemistry. NewYork: Plenum Press 1973, Chapter 5; and Greene, T. W. Protective Groupsin Organic Synthesis. New York: John Wiley & Sons, Inc. 1981. The term“protected hydroxy” refers to a hydroxy group substituted with one ofthe above hydroxy-protecting groups.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” alone and when used as a moiety in a complex group such asa heterocycloalkyl group, are used interchangeably and refer to anymono-, bi-, or tricyclic, saturated or unsaturated, aromatic(heteroaryl) or non-aromatic ring having the number of atoms designated,generally from 5 to about 14 ring atoms, where the ring atoms are carbonand at least one heteroatom (nitrogen, sulfur or oxygen), for example 1to 4 heteroatoms. Heterocyclic groups include four to seven memberedcyclic groups containing one, two or three heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. Typically, a 5-memberedring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 doublebonds. The nitrogen or sulfur heteroatoms may optionally be oxidized(e.g., SO, SO₂), and any nitrogen heteroatom may optionally bequaternized. Particular non-aromatic heterocycles are morpholinyl(morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl,tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl,piperazinyl and piperidinyl. A “heterocycloalkyl” group is a heterocyclegroup as defined above covalently bonded to an alkyl group as definedabove. Particular 5-membered heterocycles containing a sulfur or oxygenatom and one to three nitrogen atoms are thiazolyl, in particularthiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for exampleoxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and1,2,4-oxadiazol-5-yl. Particular 5-membered ring heterocycles containing2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl;triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl,1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Particularbenzo-fused 5-membered heterocycles are benzoxazol-2-yl,benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-memberedheterocycles contain one to three nitrogen atoms and optionally a sulfuror oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl,such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides andpyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl groups, are a particular group.Substituents for “optionally substituted heterocycles”, and furtherexamples of the 5- and 6-membered ring systems discussed above can befound in W. Druckheimer et al., U.S. Pat. No. 4,278,793. In a particularembodiment, such optionally substituted heterocycle groups aresubstituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo,carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino andguanidino.

“Heteroaryl” alone and when used as a moiety in a complex group such asa heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromaticring system having the number of atoms designated where at least onering is a 5-, 6- or 7-membered ring containing from one to fourheteroatoms selected from the group nitrogen, oxygen, and sulfur, and ina particular embodiment at least one heteroatom is nitrogen (Lange'sHandbook of Chemistry, supra). In one example, the heteroaryl is a fiveto six membered aromatic ring containing one, two or three heteroatomsselected from nitrogen, oxygen and sulfur. Included in the definitionare any bicyclic groups where any of the above heteroaryl rings arefused to a benzene ring. Particular heteroaryls incorporate a nitrogenor oxygen heteroatom. The following ring systems are examples of theheteroaryl (whether substituted or unsubstituted) groups denoted by theterm “heteroaryl”: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. A particular “heteroaryl” may be selectedfrom: 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,2,4-thiadiazol-5-yl,3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl,2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl,2-carboxy-4-methyl-1,3,4-triazol-5-yl,2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl,1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl,4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide,6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl. An alternative group of“heteroaryl” includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,3,4-triazol-5-yl,2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl,1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionallysubstituted as described for heterocycles.

“Inhibitor” means a compound which reduces or prevents the enzymaticconversion of cortisol to cortisone by HSD2.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3 or4) of the substituents listed for that group, as valency allows, inwhich said substituents may be the same or different. In one embodiment,an optionally substituted group has 1 substituent. In anotherembodiment, an optionally substituted group has 2 substituents. Inanother embodiment, an optionally substituted group has 3 substituents.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

“Sulfanyl” means —S—R group in which R is alkyl, a carbocycle, aheterocycle, carbocycle-substituted alkyl or heterocycle-substitutedalkyl, wherein the alkyl, alkoxy, carbocycle and heterocycle are asdefined herein. Particular sulfanyl groups are alkylsulfanyl (i.e.,—SO₂-alkyl), for example methylsulfanyl; arylsulfanyl, for examplephenylsulfanyl; aralkylsulfanyl, for example benzylsulfanyl.

“Sulfinyl” means —SO—R group in which R is hydrogen, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. Particular sulfonyl groups arealkylsulfinyl (i.e., —SO-alkyl), for example methylsulfinyl;arylsulfinyl, for example phenylsulfinyl; aralkylsulfinyl, for examplebenzylsulfinyl.

“Sulfonyl” means a —SO₂—R group in which R is hydrogen, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. Particular sulfonyl groups arealkylsulfonyl (i.e. —SO₂-alkyl), for example methylsulfonyl;arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for examplebenzylsulfonyl.

The phrase “and salts and solvates thereof” as used herein means thatcompounds of the inventions may exist in one or a mixture of salts andsolvate forms. For example a compound of the invention may besubstantially pure in one particular salt or solvate form or else may bemixtures of two or more salt or solvate forms.

In particular embodiments of the invention, compounds of Formula I havethe structures defined by Formula Ia-Ir:

wherein X, L, R₁, R₂, R₃ and R₄, are as defined herein. In a particularembodiment, the compounds have the structure according to Formula Ia. Ina particular embodiment, the compounds have the structure according toFormula Ib. In a particular embodiment, the compounds have the structureaccording to Formula Ic. In a particular embodiment, the compounds havethe structure according to Formula Id. In a particular embodiment, thecompounds have a structure according to Formula Ie. In a particularembodiment, the compounds have a structure according to Formula If. In aparticular embodiment, the compounds have a structure according toFormula Ig. In a particular embodiment, the compounds have a structureaccording to Formula Ih. In a particular embodiment, the compounds havea structure according to Formula Ii. In a particular embodiment, thecompounds have a structure according to Formula Ij. In a particularembodiment, the compounds have a structure according to Formula Ik. In aparticular embodiment, the compounds have a structure according toFormula Il. In a particular embodiment, the compounds have a structureaccording to Formula Im. In a particular embodiment, the compounds havea structure according to Formula In. In a particular embodiment, thecompounds have a structure according to Formula Io. In a particularembodiment, the compounds have a structure according to Formula Ip. In aparticular embodiment, the compounds have a structure according toFormula Iq. In a particular embodiment, the compounds have a structureaccording to Formula Ir.

In particular embodiments of the invention, compounds of Formula I havethe structures defined by Formula Ib′, Ic′, Id′, If′, Ih′, Ij′, Ik′,Il′, Im′, In′, Io′, Ip′ and Iq′:

wherein X, L, R₁, R₂, R₃, R₄ and R₅ are as defined herein. In aparticular embodiment, the compounds have the structure according toFormula Ib′. In a particular embodiment, the compounds have thestructure according to Formula Ic′. In a particular embodiment, thecompounds have the structure according to Formula Id′. In a particularembodiment, the compounds have the structure according to Formula If′.In a particular embodiment, the compounds have a structure according toFormula Ih′. In a particular embodiment, the compounds have a structureaccording to Formula Ij′. In a particular embodiment, the compounds havea structure according to Formula Ik′. In a particular embodiment, thecompounds have a structure according to Formula Il′. In a particularembodiment, the compounds have a structure according to Formula Im′. Ina particular embodiment, the compounds have a structure according toFormula Io′. In a particular embodiment, the compounds have a structureaccording to Formula Ip′. In a particular embodiment, the compounds havea structure according to Formula Iq′.

In an embodiment, the compound of the invention has a formula of any oneof formula I

In an embodiment, X is a bond, —O—, —N(R_(x))—, —C(O)N(R_(x))—,—N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—; whereinR_(x) is H, —C(O)O—R₁, or alkyl optionally substituted with —C(O)O—R₁;In an embodiment, X is a bond. In an embodiment, X is —O—. In anembodiment, X is —N(R_(x))—. In an embodiment, X is —NH—. In anembodiment, X is —C(O)N(R_(x))—. In an embodiment, X is —C(O)NH—. In anembodiment, X is —N(R_(x))—C(O)—. In an embodiment, X is —NH—C(O)—. Inan embodiment, X is —S(O)_(n)—N(R_(x))—. In an embodiment, X is—S(O)—NH—. In an embodiment, X is —S(O)₂—NH—. In an embodiment, X is—N(R_(x))—S(O)_(n)—. In an embodiment, X is —NH—S(O)—. In an embodiment,X is —NH—S(O)₂—.

V is —C(O)O—, —C(O)N(R₅)—, —C(O)N(R₅)O—, —NH—C(O)—N(R₅)— orNH—S(O)_(n)—.

In an embodiment, V is —C(O)O—. In an embodiment, V is —C(O)O— and R₂ isH. In an embodiment, V is —C(O)O— and R₂ is a prodrug group. In anembodiment, V is —C(O)O— and R₂ is alkyl. In an embodiment, V is —C(O)O—and R₂ is methyl. In another embodiment V is —C(O)O— and R₂ is alkyloptionally substituted with oxo, acyloxy, alkoxycarbonyl, alkoxyacyloxy,alkoxycarbonyloxy, a carbocycle optionally substituted with alkyl andoxo, and a heterocycle optionally substituted with alkyl and oxo.

In an embodiment, V is —C(O)N(R₅)—. In an embodiment, V is —C(O)N(R₅)—and both R₂ and R₅ are H. In an embodiment, V is —C(O)N(R₅)— and R₂ andR₅ are independently H and alkyl optionally substituted with OH. In anembodiment, V is —C(O)N(R₅)— and R₅ is H and R₂ is hydroxyethyl.

In an embodiment, V is —C(O)N(R₅)O—. In an embodiment, V is —C(O)N(R₅)O—and R₂ and R₅ are independently H or alkyl. In an embodiment, V is—C(O)N(R₅)O— and R₂ is methyl and R₅ is H.

In an embodiment, V is —NH—C(O)—N(R₅)— and R₂ and R₅ are independently Hor alkyl. In an embodiment, V is —NH—C(O)—N(R₂)— and R₂ is methyl and R₅is H. In an embodiment, V is —NH—C(O)—N(R₅)— and both R₂ and R₅ are H.

In an embodiment, V is NH—S(O)_(n)—. In an embodiment, V is NH—S(O)₂—.In an embodiment, V is NH—S(O)₂— and R₂ is alkyl. In an embodiment, V isNH—S(O)₂— and R₂ is methyl.

L is a bond, alkylene wherein one or more non-adjacent methylene groupsof said alkylene are replaced with —O—; divalent aryl or divalentheteroaryl; or L is alkylene-Y-alkylene wherein Y is O, NR_(x), S, SO,SO₂ or a divalent heterocycle; wherein said alkylene groups areoptionally substituted with OH, —C(O)O—R₁, alkyl or alkyl substitutedwith OH or —C(O)O—R₁; and wherein a carbon of said alkylene groups andR_(x) optionally together form a heterocycle; provided that when X isother than a bond, then L is other than a bond;

In an embodiment, L is a bond or alkylene wherein one or morenon-adjacent methylene groups of said alkylene are replaced with —O—. Inan embodiment, L is a bond. In an embodiment, L is alkylene. In anembodiment, L is alkylene. In an embodiment, L is alkylene in which oneor more non-adjacent methylene groups of said alkylene are replaced with—O—. In an embodiment, L is —[(CH₂)₂—O]₁₋₅—. In an embodiment, L is—(CH₂)₂—O—. In an embodiment, L is —[(CH₂)₂—O]₂—. In an embodiment, L is—[(CH₂)₂—O]₃—. In an embodiment, L is —[(CH₂)₂—O]₄—. In an embodiment, Lis —[(CH₂)₂—O]₅—.

In an embodiment, L is alkylene-Y-alkylene wherein Y is O, NR_(x), S,SO, SO₂ or a divalent heterocycle; wherein said alkylene groups areoptionally substituted with OH, —C(O)O—R₁, alkyl or alkyl substitutedwith OH or —C(O)O—R₁; and wherein a carbon of said alkylene groups andR_(x) optionally together form a heterocycle; provided that when X isother than a bond, then L is other than a bond. In an embodiment, L isalkylene-Y-alkylene wherein Y is O. In an embodiment, L isalkylene-Y-alkylene wherein Y is NR_(x). In an embodiment, L isalkylene-Y-alkylene wherein Y is NR_(x) wherein a carbon of saidalkylene groups and R_(x) together form a heterocycle. In an embodiment,L is alkylene-Y-alkylene wherein Y is S. In an embodiment, L isalkylene-Y-alkylene wherein Y is SO. In an embodiment, L isalkylene-Y-alkylene wherein Y is SO₂. In an embodiment, L isalkylene-Y-alkylene wherein Y is divalent heterocycle. In an embodiment,L is a aryl. In an embodiment, L is phenyl. In an embodiment, L is1,4-phenylene. In an embodiment, L is heteroaryl. In an embodiment, L istriazole. In an embodiment, L is isoxazole.

R₁ is alkyl optionally substituted with halogen, OH, amino, oxo,carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy,aminocarbonyl, a carbocycle optionally substituted with alkyl,haloalkyl, oxo, amino and halogen and a heterocycle optionallysubstituted with alkyl, oxo, amino and halogen; and a carbocycle orheterocycle optionally substituted with alkyl, haloalkyl, oxo, amino andhalogen; wherein one or more non-adjacent methylene groups in any of theforegoing alkyl groups is replaced with O. In an embodiment, R₁ isalkyl. In an embodiment, R₁ is alkyl substituted with OH. In anembodiment, R₁ is alkyl substituted with oxo. In an embodiment, R₁ isalkyl substituted with carboxy. In an embodiment, R₁ is alkylsubstituted with acyloxy. In an embodiment, R₁ is alkyl substituted withalkoxycarbonyl. In an embodiment, one or more non-adjacent methylenegroups in any of the alkyl groups in R₁ is replaced with O. In anembodiment, R₁ is alkyl substituted with alkoxyacyloxy. In anembodiment, R₁ is alkyl substituted with alkoxycarbonyloxy. In anembodiment, R₁ is alkyl substituted with aminocarbonyl. In anembodiment, R₁ is methyl. In an embodiment, R₁ is propyl. In anembodiment, R₁ is hydroxyethyl. In an embodiment, R₁ is2,2,2-trifluoroethyl. In an embodiment, R₁ is 1,1-trifluoromethylethyl.In an embodiment, R₁ is 2-morpholinoethyl. In an embodiment, R₁ is2-(1H-imidazol-1-yl)ethyl. In an embodiment, R₁ is2-(pyridin-2-yl)ethyl. In an embodiment, R₁ is —CH₂—C(O)OH.

In an embodiment, R₁ is —CH₂—C(O)O-Me. In an embodiment, R₁ is—CH₂—C(O)NH₂. In an embodiment, R₁ is-CH₂—C(O)NMe₂. In an embodiment, R₁is —CH₂—C(O)O-t-butyl. In an embodiment, R₁ is(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl. In an embodiment, R₁ is(pivaloyloxy)methyl. In an embodiment, R₁ is((isopropoxycarbonyl)oxy)methyl. In an embodiment, R₁ is(S)-1-((isopropoxycarbonyl)oxy)ethyl. In an embodiment, R₁ is(R)-1-((isopropoxycarbonyl)oxy)ethyl. In an embodiment, R₁ is2-morpholino-2-oxoethyl. In an embodiment, R₁ is2-(4-methylpiperazin-1-yl)-2-oxoethyl. In an embodiment, R₁ is(R)-quinuclidin-3-yl.

In an embodiment, R₁ is —[(CH₂)₂—O]p-Me wherein p is 1 to 20. In anembodiment p is 1 to 19. In an embodiment p is 1 to 18. In an embodimentp is 1 to 17. In an embodiment p is 1 to 16. In an embodiment p is 1 to15. In an embodiment p is 1 to 14. In an embodiment p is 1 to 13. In anembodiment p is 1 to 12. In an embodiment p is 1 to 11. In an embodimentp is 1 to 10. In an embodiment p is 1 to 9. In an embodiment p is 1 to8. In an embodiment p is 1 to 7. In an embodiment p is 1 to 6. In anembodiment p is 1 to 5. In an embodiment p is 1 to 4. In an embodiment pis 1 to 3. In an embodiment p is 1 to 2. In an embodiment p is 1 to 1.

In an embodiment, R₂ is H or R₁. In an embodiment, R₂ is H. In anembodiment, R₂ is R₁. In an embodiment, R₂ is methyl. In an embodiment,R₂ is t-butyl. In an embodiment, R₂ is benzhydryl. In an embodiment, R₂is benzyl.

R₃ is absent, Me; provided that when X depends from the carbon to whichR₃ depends then R₃ is absent; or R₃ is —Z-L-C(O)O—R₁ wherein Z is abond, —O—, —N(R_(x))—, —C(O)N(R_(x))—, —N(R_(x))—C(O)—,—S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—. In an embodiment, R₃ ismethyl. In an embodiment, R₃ is absent and X depends from the carbon towhich R₃ depends. In an embodiment, R₃ is —Z-L-C(O)O—R₁ wherein Z is abond, —O—, —N(R_(x))—, —C(O)N(R_(x))—, —N(R_(x))—C(O)—,—S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—. In an embodiment, Z is —O—.In an embodiment, Z is —N(R_(x))—. In an embodiment, Z is —NH—. In anembodiment, R₃ is —C(O)N(R_(x))—. In an embodiment, R₃ is —C(O)NH—. Inan embodiment, R₃ is —N(R_(x))—C(O)—. In an embodiment, R₃ is —NH—C(O)—.In an embodiment, R₃ is —S(O)_(n)—N(R_(x))—. In an embodiment, R₃ is—S(O)—NH—. In an embodiment, R₃ is —S(O)₂—NH—. In an embodiment, R₃ is—N(R_(x))—S(O)_(n)—. In an embodiment, R₃ is —NH—S(O)₁—. In anembodiment, R₃ is —NH—S(O)₂—.

R₄ is absent, H or OH; provided that when —X-L-C(O)O—R₁ depends from thecarbon to which R₄ depends then R₄ is H or absent;

In an embodiment, R₄ is H. In an embodiment, R₄ is H and the carbon fromwhich it depends is part of a double bond. In an embodiment, R₄ is H andthe carbon from which it depends is not part of a double bond. In anembodiment, R₄ is OH. In an embodiment, R₄ is absent and Xdepends-X-L-C(O)O—R₁ depends from the carbon to which R₄ depend and saidcarbon is part of a double bond.

R₅ is H or alkyl optionally substituted with a carbocycle or heterocyclewherein said carbocycle and heterocycle are optionally substituted withoxo and alkyl. In an embodiment, R₅ is H. In an embodiment, R₅ is alkyl.In an embodiment, R₅ is methyl. In an embodiment, R₅ is

In an embodiment, R_(x) is H. In an embodiment, R_(x) is —C(O)O—R₁. Inan embodiment, R_(x) is alkyl. In an embodiment, R_(x) is alkyloptionally substituted with —C(O)O—R₁.

In an embodiment ‘n’ is 1. In another embodiment, ‘n’ is 2.

In an embodiment, the compound of the invention is one of the followingcompounds:

-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Isopropoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-Hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,    9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Hydroxyethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-Imidazol-1-yl)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholinoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,    14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Amino-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((Carboxymethoxy)carbonyl)-4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-Butoxy)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)(methyl)-carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b, 13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(Methoxycarbonyl)pyrrolidine-1-carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-Dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-Dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-Methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,    9,10,11,12,12a, 12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-Hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,    9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-Hydroxyethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,    6b,7,8,8a,9,10,11,12,12a, 12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,    9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(((pivaloyloxy)methoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)    carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)-ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,    6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((Isopropoxycarbonyl)oxy)ethoxy)    carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,    12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(Diethylamino)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholino-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   Dibenzyl 2,2′-(((3    S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,    6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)azanediyl)diacetate;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Methoxy-2,2-dimethyl-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Methoxy-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-Methoxy-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-Methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   Benzyl    (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutan    amido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-Methoxy-3,3-dimethyl-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-Methoxy-3-oxopropyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-Methoxy-2-oxoethoxy)acetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-Methoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-Methoxy-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-Dimethoxy-1,3-dioxopropan-2-yl)oxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(Ethoxycarbonyl)piperidin-1-yl)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((3-oxo-2,6,9,12-tetraoxatetradecan-14-yl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatetradecane)sulfonamido)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(4-oxo-2,8,11,14-tetraoxa-5-azapentadecanoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-Hydroxy-9-(methoxycarbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-oxo-2-(((R)-quinuclidin-3-yl)oxy)ethyl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid.

In another embodiment, the compound of the invention is one of thefollowing compounds:

-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,    12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((10-methyl-12-oxo-2,5,8,11-tetraoxatridecan-13-yl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2,5,9,12-tetraoxatridecan-7-yloxy)-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-ethoxy-2-oxoethoxy)ethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-(2-methoxyethoxy)-2-oxoethoxy)ethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-((1-methoxypropan-2-yl)oxy)-2-oxoethoxy)ethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-(2-(2-methoxyethoxy)ethoxy)-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,    7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(2,5,8,11-tetraoxadodecan-1-oyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(4-oxo-2,5,8,11,14-pentaoxapentadecan-1-oyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,    13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(5-methyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,    11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(3-methyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(3,5-dimethyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,    8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(2,5,8,11,14-pentaoxapentadecan-1-oyl)piperidin-1-yl)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-9-(methoxycarbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,    12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5,8,11-tetraoxatetradecan-14-oyloxy)-9-(methoxycarbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{3-[4,4-bis(methoxycarbonyl)piperidin-1-yl]-2-hydroxypropoxy}-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,    8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{[(2-methoxy-2-oxoethyl)carbamoyl]oxy}-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic    acid;-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-9-[(ethylsulfanyl)carbonyl]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,    12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-[3-(tert-butoxy)-3-oxopropoxy]-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,    8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid;-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(3R)-3-(methoxycarbonyl)pyrrolidin-1-yl]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,    10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid; and-   (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(methoxycarbonyl)piperidin-1-yl]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,    12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid.

Many of the compounds listed above (greater than 50%) were tested in theassays described in examples 59 to determine their activity ininhibiting HSD2 by measuring the amount of cortisol before and aftercontacting cell lysate (human and rat) or a colon monolayer organoidderived from human colon tissue. HSD2 inhibition for the compounds ofthe invention as expressed as pIC₅₀ ranged from 8.9 to 7.7 (humanlysate) and 8.9 to 7.5 (rat lysate) and >8 to 5.9 (human organoid). Forreference, glycyrrhetinic acid was tested in the same HSD2 assays: 8.5(human lysate), 6.4 (human organoid). The pIC₅₀ differential between thecompounds of the invention and their corresponding acid compound rangedfrom 2.2 to 0.4 (human lysate), 1.3 to 0.8 (human organoid) with theexception of one compound tested having negative pIC50 differentials(less HSD2 inhibitory activity) in both lysates but 1.3 in the humanorganoid. The positive differentials demonstrate greater HSD2 inhibitoryactivity of the compound of the invention compared to the correspondingacid compound.

Compounds of the invention may contain one or more asymmetric or chiralcenters. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Diastereomeric compounds may be separated bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated using the same techniques or others known inthe art. Unless specified, each of the asymmetric centers may be in theR or S configuration and both of these configurations are within thescope of the invention. It is intended that all stereoisomeric forms ofthe compounds described herein, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixturesthereof, such as racemic mixtures, form part of the present compounds.

It will also be appreciated that certain compounds of Formula I may beused as intermediates for further compounds of Formula I. It will befurther appreciated that the compounds described herein may exist inunsolvated, as well as solvated forms with pharmaceutically acceptablesolvents, such as water, ethanol, and the like, and it is intended thatthe compounds embrace both solvated and unsolvated forms.

Compounds of the invention are prepared using standard organic synthetictechniques from commercially available starting materials and reagents.It will be appreciated that synthetic procedures employed in thepreparation of compounds of the invention will depend on the particularsubstituents present in a compound and that various protection anddeprotection steps that are standard in organic synthesis may berequired but may not be illustrated in the following general schemes.The starting materials are generally available from commercial sourcesor are readily prepared using methods well known to those skilled in theart. For illustrative purposes, schemes herein shows a general methodfor preparing the compounds of the invention, as well as keyintermediates. Those skilled in the art will appreciate that othersynthetic routes may be used to synthesize the compounds. Althoughspecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the compounds prepared by the methodsdescribed below can be further modified in light of this disclosureusing conventional chemistry well known to those skilled in the art. Ingeneral, the compounds of the invention may be prepared according toscheme 1 starting with a carboxylic acid derivative of glycyrrhetinicacid (i) which is converted to the corresponding acid halide e.g. acidchloride intermediate (ii), for example, with oxalyl chloride catalyzedby dimethylformamide. Intermediate (ii) is then reacted with alcoholintermediate (iii) to give final ester compound of formula I.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. The need for such protection is readilydetermined by one skilled in the art. For a general description ofprotecting groups and their use, see Greene, T. W., and P. G. M. Wuts.Greene's Protective Groups in Organic Synthesis. 4th ed. New York:Wiley-Interscience, 2006.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Diastereomeric and enantiomeric mixtures can be separated into theirindividual stereoisomers on the basis of their physical chemicaldifferences by methods well known to those skilled in the art, such asby chromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

The invention also includes pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments.Typically, the compounds of Formula I used in the methods of theinvention are formulated by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed. The pH of theformulation depends mainly on the particular use and the concentrationof compound, but may range anywhere from about 3 to about 8. Formulationin an acetate buffer at pH 5 is a suitable embodiment. In oneembodiment, formulations comprising compounds of the invention aresterile. The compounds ordinarily will be stored as a solid composition,although lyophilized formulations or aqueous solutions are acceptable.

Compositions comprising compounds of the invention will be formulated,dosed, and administered in a fashion consistent with good medicalpractice. Factors for consideration in this context include theparticular disorder being treated, the particular mammal being treated,the clinical condition of the individual patient, the cause of thedisorder, the site of administration, the method of administration, thescheduling of administration, and other factors known to medicalpractitioners. The “effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to inhibit conversion of cortisol to cortisone by HSD2. Suchamount may be below the amount that is toxic to normal cells, or themammal as a whole.

The compound of the invention may be administered by any suitable means.In a particular embodiment, the compounds are administered orally. In aparticular embodiment, the compounds are administered rectally.

Generally, the initial pharmaceutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01-1,000 mg/kg/day, for example about 0.1 to 100 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.5 to 50 mg/kg/day. Oral unit dosage forms, such as tabletsand capsules, may contain from about 25 to about 1000 mg of the compoundof the invention. In a particular embodiment, an effective amount is theamount of the compound of the invention sufficient to enhance colonicpotassium secretion by about 15 mmol/day. In a particular embodiment, aneffective amount is the amount of the compound of the inventionsufficient to enhance colonic potassium secretion by about 1 mmol/day.In a particular embodiment, an effective amount is the amount of thecompound of the invention sufficient to enhance colonic potassiumsecretion by about 5 mmol/day. In a particular embodiment, an effectiveamount is the amount of the compound of the invention sufficient toenhance colonic potassium secretion by about 10 mmol/day. In aparticular embodiment, an effective amount is the amount of the compoundof the invention sufficient to enhance colonic potassium secretion byabout 15 mmol/day. In a particular embodiment, an effective amount isthe amount of the compound of the invention sufficient to enhancecolonic potassium secretion by about 20 mmol/day.

The compounds may be administered in any convenient administrative form,e.g., tablets, capsules, solutions, dispersions, suspensions, syrups,suppositories, gels, emulsions etc. An example of a suitable oral dosageform is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500mg of the compound of the invention compounded with about 90-30 mganhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mgpolyvinylpyrrolidone (“PVP”) K30, and about 1-10 mg magnesium stearate.The powdered ingredients are first mixed together and then mixed with asolution of the PVP. The resulting composition can be dried, granulated,mixed with the magnesium stearate and compressed to tablet form usingconventional equipment.

Another formulation may be prepared by mixing a compound describedherein and a carrier or excipient. Suitable carriers and excipients arewell known to those skilled in the art and are described in detail in,e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

In an embodiment, the formulation releases the compound in response tocontact with colonic enzyme, for example, enzymes created byenterobacteria. Certain starch-based capsule coatings may be used thatare resistant to digestion in the stomach and small intestine but aredegraded by microbial (normal gut flora) enzymes once the dosage formreaches the colon.

In an embodiment, the compound of the invention is administered orally.In another embodiment, the compound is formulated for colonic delivery.Colonic delivery may be effected in response to pH time, microbes, andpressure. In an embodiment, the formulation releases the compound inresponse to colonic pH. Release of the compound is triggered by the pHincrease as the formulation travels through the GI tract. Formulationsare based on polymers that are insoluble at the lower pH in the stomachand upper small intestine and soluble in the higher pH found in thedistal small intestine, for example, polymers that are derivatives ofacrylic acid and cellulose which withstand an environment as low as pH˜1.2. Suitable enteric polymers include, polyvinyl acetate phthalate(PVAP) e.g. Coateric®, cellulose acetate trimellitate (CAT),hydroxypropyl methylcellulose phthalate (HPMCP) e.g. HP-50, HP-55,HP-55S, hydroxypropylmethylcellulose acetate succinate (HPMCAS) e.g. LFgrade, MF grade or HF grade, methacrylic acid copolymer e.g. Eudragit®L100-55, L30D-55, L-1000, L12.5, S-100, S12.5, FS30D, cellulose acetatephthalate (CAP) e.g. Aquateric®, and shellac e.g. MarCoat® 125 or 125N.

In an aspect of the invention, there is provided a method of inhibitingconversion of cortisol to cortisone by HSD2 comprising contacting HSD2with a compound of Formula I. In another aspect of the invention, thereis provided a method for promoting activation MR in a mammal, comprisingadministering to said mammal an effective amount of a compound ofFormula I. In another aspect of the invention, there is provided amethod of reducing potassium levels in plasma of a mammal, comprisingadministering to said mammal an effective amount of a compound ofFormula I. In another aspect of the invention, there is provided amethod for promoting potassium ion secretion into the colonic lumen of amammal, comprising administering to said mammal an effective amount of acompound of Formula I.

In an aspect of the invention, there is provided a method for treatingand/or preventing hyperkalemia in a mammal, comprising administering tosaid mammal an effective amount of a compound of Formula I. Hyperkalemiaoccurs especially frequently in patients with chronic kidney disease(CKD), hypertension, heart failure and diabetes. Accordingly, in anembodiment of the invention the methods of treating and/or preventinghyperkalemia is in a patient having CKD hypertension, heart failure anddiabetes. Patients suffering for these conditions are often treated withcertain classes of medications, such as angiotensin-converting-enzyme(ACE) inhibitors, angiotensin-receptor blockers (ARBs) or otherinhibitors of the renin-angiotensin-aldosterone system (RAAS) in orderto regulate blood pressure. However such medications promote potassiumretention. Accordingly, there is provided a method of treating and/orpreventing hyperkalemia in a mammal comprising administering a compoundof formula I in combination with an inhibitor of the RAAS system. In anembodiment, the RAAS inhibitor is an ACE inhibitor.

The compounds described herein and stereoisomers, diastereomers,enantiomers, tautomers and pharmaceutically acceptable salts thereof maybe employed alone or in combination with other anti-hyperkalemia agentsthat works by a different mechanism of action. The compound of theinvention may be administered together with the other anti-hyperkalemiaagent in a unitary pharmaceutical composition or separately and, whenadministered separately this may occur simultaneously or sequentially inany order. Such sequential administration may be close in time or remotein time.

In an embodiment, the other anti-hyperkalemic compound is a potassiumion binder such as a cross-lined polystyrene sulfonate (PSS) polymerresins. In an embodiment, the PSS resin is crosslinked withdivinylbenzene (DVB) co-polymer. DVB-crosslinked PSS is the most commonagent used in the management of hyperkalemia in hospitalized patients.PSS is typically provided as a sodium or calcium salt, and in the lumenof the intestine it exchanges sodium or calcium ions for secretedpotassium ions. Most of this takes place in the colon, the site of mostpotassium secretion in the gut. In an embodiment, the anti-hyperkalemicPSS resin is described in WO2016111855 (incorporated herein byreference). In an embodiment, the PSS resin is a calcium salt of a PSSpolymer resins crosslinked with DVB co-polymer. In an embodiment, thePSS resin is cross-linked with from 1.0 to 1.9 percent of DVB. In anembodiment, the PSS resin is cross-linked with from 1.6 to 1.9 percentof DVB. In an embodiment, the PSS resin is cross-linked with about 1.8percent of DVB.

In an embodiment, the other anti-hyperkalemia agent is Kayexalate®,Argamate®, Kionex®, Resonium® or RDX7675. In another embodiment, theother anti-hyperkalemia agent is a fluoroacrylate polymer incorporatinga potassium-binding carboxylate group e.g. patiromer (Veltassa®). In anembodiment, the other anti-hyperkalemia agent is an insoluble,non-absorbed zirconium-sodium silicate that traps potassium ions withinits crystalline lattice structure e.g. ZS-9 (Lokelma®). In anembodiment, the other anti-hyperkalemia agent is a crosslinkedpolyacrylic acid e.g. CLP-1001.

In another aspect of the invention, it has been found unexpectedly thatHSD2 inhibition in combination with inhibition of sodium-hydrogenexchanger (NHE) synergistically increase excretion of potassium intofeces. NHE is found in the tubulus proximal of the nephron of the kidneyand in the apical membrane of enterocytes of the intestine. The isoformknown as NHE3 is primarily responsible for maintaining the balance ofsodium and also indirectly linked to buffering of blood pH. The NHE3antiporter imports one sodium ion into the cytosol of a cell as itejects one hydrogen ion from the cell into the intestinal lumen andproximal tubule lumen. As shown in FIG. 1 , it has been demonstratedthat there is a synergistic effect on fecal potassium excretion wheninhibiting HSD2 and NHE. Accordingly, there is provided a method forremoving potassium from plasma and/or tissue of a mammal comprisingadministering to said mammal an effective amount of an HSD2 inhibitor oran MR agonist in combination with a compound that increases fluid volumein the colon. There is also provided a method for removing potassiumfrom plasma and/or tissue of a mammal comprising administering to saidmammal an effective amount of an HSD2 inhibitor or an MR agonist incombination with a compound that removes sodium from plasma and/ortissue. There is also provided a method for removing potassium fromplasma and/or tissue of a mammal comprising administering to said mammalan effective amount of an HSD2 inhibitor or an MR agonist in combinationwith a compound that promotes excretions of sodium into thegastrointestinal tract. In an embodiment, the compound is a laxativethat increases fluid in the colon. In an embodiment, the laxative isbisacodyl. In an embodiment, the laxative is picosulfate. In anembodiment, the laxative is MgOH. In an embodiment, the laxative isMiraLAX® (PEG 3350). In an embodiment, the laxative is lactulose. In anembodiment, the compound is an activator of intestinal guanylatecyclase. In an embodiment the guanylate cyclase agonist is linaclotide.In an embodiment, the guanylate cyclase agonist is plecanatide. In anembodiment, the compound is an activator of intestinal ClC-2 chloridechannel. In an embodiment, the ClC-2 chloride channels activator islubiprostone.

There is also provided a method for removing potassium from plasmaand/or tissue of a mammal comprising administering to said mammal aneffective amount of an HSD2 inhibitor or an MR agonist in combinationwith a an NHE inhibitor. In an embodiment, the HSD2 inhibitor or MRagonist and the NHE inhibitor compounds are administered concurrently.In an embodiment, the HSD2 or MR agonist and the NHE inhibitor compoundsare administered sequentially. In an embodiment, the HSD2 inhibitor orMR agonist is administered prior to the NHE inhibitor or MR agonist. Inan embodiment, the NHE inhibitor or MR agonist compound is administeredprior to the HSD2 inhibitor or MR agonist. In an embodiment, the NHEinhibitor is an NHE3 inhibitor.

In another aspect of the invention, there is provided a pharmaceuticalcomposition comprising an HSD2 inhibitor and an NHE inhibitor. Inanother aspect, there is provided a pharmaceutical compositioncomprising an MR agonist and an NHE inhibitor.

In another aspect, there is provided a method for treating hyperkalemiain a mammal comprising administering to said mammal an effective amountof an HSD2 inhibitor or an MR agonist in combination with an NHEinhibitor. In an embodiment, the NHE inhibitor is an NHE3 inhibitor.

In an embodiment, the MR agonist is fludrocortisone.

In another aspect, there is provided a method for treating hyperkalemiain a mammal comprising administering to said mammal an effective amountof an HSD2 inhibitor in combination with an NHE inhibitor. In anembodiment, the NHE inhibitor is an NHE3 inhibitor. In another aspect,there is provided a composition comprising an HSD2 inhibitor and an NHEinhibitor. In an embodiment, the composition is a pharmaceuticalcomposition. In an embodiment there is an effective amount of HSD2inhibitor compound and the NHE inhibitor compound. In an embodiment, thecomposition further comprises a pharmaceutically acceptable carrier,excipient and/or diluent. In an embodiment, the HSD2 inhibitor isglycyrrhetinic acid or an analogue thereof. In an embodiment, the HSD2inhibitor is glycyrrhetinic acid. In an embodiment, the HSD2 inhibitoris glycyrrhizin. In an embodiment, the HSD2 inhibitor is a compoundaccording to formula I herein. In an embodiment, the NHE inhibitor is anNHE3 inhibitor. In an embodiment the NHE3 inhibitor is a compounddescribed in: U.S. Pat. Nos. 5,866,610; 6,399,824; 6,911,453; 6,703,405;6,005,010; 6,736,705; 6,887,870; 6,737,423; 7,326,705; 5,824,691(WO94/026709); 6,399,824 (WO02/024637); U.S. Pat. Pub. Nos. 2004/0039001(WO02/020496); 2005/0020612 (WO03/055490); 2004/0113396 (WO03/051866);2005/0020612; 2005/0054705; 2008/0194621; 2007/0225323; 2004/0039001;2004/0224965; 2005/0113396; 2007/0135383; 2007/0135385; 2005/0244367;2007/0270414; International Publication Nos. WO 01/072742; WO 01/021582(CA2387529); WO97/024113 (CA02241531) WO2010078449; WO2014029983;WO2014029984; and European Pat. No. EP0744397 (CA2177007); each of whichis incorporated herein by reference in their entirety.

In an embodiment, the NHE inhibitor is a compound that is minimallysystemic, i.e., it inhibits NHE in the intestine and is substantiallynon-bioavailable. In an embodiment, the NHE inhibitor is a compoundFormula (I) or (IX):

wherein:

-   -   NHE is a NHE-binding small molecule that comprises (i) a        hetero-atom containing moiety, and (ii) a cyclic or heterocyclic        scaffold or support moiety bound directly or indirectly thereto,        the heteroatom-containing moiety being selected from a        substituted guanidinyl moiety and a substituted heterocyclic        moiety, which may optionally be fused with the scaffold or        support moiety to form a fused bicyclic structure; and,    -   Z is a moiety having at least one site thereon for attachment to        the NHE-binding small molecule, the resulting NHE-Z molecule        possessing overall physicochemical properties that render it        substantially impermeable or substantially systemically        non-bioavailable; and,    -   E is an integer having a value of 1 or more.

In certain embodiments, the total number of freely rotatable bonds inthe NHE-Z molecule is at least about 10. In certain embodiments, thetotal number hydrogen bond donors in the NHE-Z molecule is at leastabout 5. In some embodiments, the total number of hydrogen bondacceptors in the NHE-Z molecule is at least about 10. In certainembodiments, the total number of hydrogen bond donors and hydrogen bondacceptors in the NHE-Z molecule is at least about 10. In someembodiments, the Log P of the NHE-Z binding compound is at least about5. In certain embodiments, the log P of the NHE-Z binding compound isless than about 1, or less than about 0. In certain embodiments, thescaffold is a 5-member or 6-member cyclic or heterocyclic moiety. Incertain embodiments, the scaffold is aromatic.

In some embodiments, the scaffold of the NHE-binding small molecule isbound to the moiety, Z, the compound having the structure of Formula(II):

wherein:

-   -   Z is a Core having one or more sites thereon for attachment to        one or more NHE-binding small molecules, the resulting NHE-Z        molecule possessing overall physicochemical properties that        render it substantially impermeable or substantially        systemically non-bioavailable;    -   B is the heteroatom-containing moiety of the NHE-binding small        molecule, and is selected from a substituted guanidinyl moiety        and a substituted heterocyclic moiety, which may optionally be        fused with the Scaffold moiety to form a fused, bicyclic        structure;    -   Scaffold is the cyclic or heterocyclic scaffold or support        moiety of the NHE-binding small molecule, which is bound        directly or indirectly to heteroatom-containing moiety, B, and        which is optionally substituted with one or more additionally        hydrocarbyl or heterohydrocarbyl moieties;    -   X is a bond or a spacer moiety selected from a group consisting        of substituted or unsubstituted hydrocarbyl or heterohydrocarbyl        moieties, and in particular substituted or unsubstituted C₁₋₇        hydrocarbyl or heterohydrocarbyl, and substituted or        unsubstituted, saturated or unsaturated, cyclic or heterocyclic        moieties, which links B and the Scaffold; and    -   D and E are integers, each independently having a value of 1 or        more.

In some embodiments, the compound is an oligomer, dendrimer or polymer,and further wherein Z is a Core moiety having two or more sites thereonfor attachment to multiple NHE-binding small molecules, either directlyor indirectly through a linking moiety, L, the compound having thestructure of Formula (X):

wherein L is a bond or linker connecting the Core to the NHE-bindingsmall molecule, and n is an integer of 2 or more, and further whereineach NHE-binding small molecule may be the same or differ from theothers.

In some embodiments, the NHE-binding small molecule has the structure ofFormula (IV):

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein:

-   -   each R₁, R₂, R₃, R₅ and R₉ are independently selected from H,        halogen, —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈,        —OR₇, —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇        and R₈ are independently selected from H or a bond linking the        NHE-binding small molecule to L, provided at least one is a bond        linking the NHE-binding small molecule to L;    -   R₄ is selected from H, C₁-C₇ alkyl, or a bond linking the        NHE-binding small molecule to L;    -   R₆ is absent or selected from H and C₁-C₇ alkyl; and    -   Ar1 and Ar2 independently represent an aromatic ring or a        heteroaromatic ring.

In certain embodiments, the NHE-binding small molecule has the followingstructure:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein:

-   -   each R₁, R₂ and R₃ are independently selected from H, halogen,        —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈, —OR₇,        —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇ and R₈        are independently selected from H or a bond linking the        NHE-binding small molecule to L, provided at least one is a bond        linking the NHE-binding small molecule to L.

In some embodiments, the NHE-binding small molecule has one of thefollowing structures:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.In certain embodiments, L is a polyalkylene glycol linker. In certainembodiments, L is a polyethylene glycol linker. In some embodiments, nis 2.

In certain embodiments, the Core has the following structure:

wherein:

-   -   X is selected from the group consisting of a bond, —O—, —NH—,        —S—, C₁₋₆alkylene, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —SO₂NH—,        and —NHSO₂—;    -   Y is selected from the group consisting of a bond, optionally        substituted C₁₋₈alkylene, optionally substituted aryl,        optionally substituted heteroaryl, a polyethylene glycol linker,        —(CH₂)₁₋₆O(CH₂)₁₋₆— and —(CH₂)₁₋₆NY₁(CH₂)₁₋₆—; and    -   Y₁ is selected from the group consisting of hydrogen, optionally        substituted C₁₋₈alkyl, optionally substituted aryl or optionally        substituted heteroaryl.

In some embodiments, the Core is selected from the group consisting of:

wherein: L is a bond or a linking moiety; NHE is a NHE-binding smallmolecule; and n is a non-zero integer.

In an embodiment, the NHE inhibitor is:

-   N,N′,N″-(2,2′,2″-nitrilotris(ethane-2,1-diyl))tris(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(butane-1,4-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(dodecane-1,12-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′,N″,N′″-(3,3′,3″,3′″-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(butane-1,4-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(dodecane-1,12-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′,N″-(2,2′,2″-nitrilotris(ethane-2,1-diyl))tris(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′,N″,N′″-(3,3′,3″,3′″-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(1,4-phenylenebis(methylene))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N1,N8-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)octanediamide;-   2-(N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonic    acid;-   2-(N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonic    acid;-   N,N′-(butane-1,4-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(1,4-phenylenebis(methylene))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(2,2′-(2,2′-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide]-   (E)-3-(4-(4-(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide;-   N,N′-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(13,20 dioxo-3, 6, 9, 24, 27, 30-hexaoxa-12,    21-diazadotricontane-1,32-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(2,2′-(2,2′-(2,2′-(2,2′-(4,4′-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];-   N,N′-(2,2′-(2,2′-(2,2′-(2,2′-(4,4′-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide)-   1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4,5-dicarboxylic    acid;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N31-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide;-   N1,N31-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide;-   N,N′-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N1,N31-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide;-   N,N′-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)-3,6,9,12,15,18-hexaoxaicosyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-quinolin-4-yl)phenylsulfonamido)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   3,3′-(2,2′-(2,2′-(2,2′-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4,2-diyl))dianiline;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-1-oxo-5,8,11-trioxa-2-azatridecan-13-yl)-2,3-dihydroxysuccinamide;-   N1,N2-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxalamide;-   N1,N4-bis(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;-   2,2′-oxybis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);-   (2R,3R)—N1,N4-bis(2-(2-(2-(3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxalamide;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;-   N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;-   N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;-   N,N′-(2,2′-(2,2′-(2,2′-(2,2′-(pyridine-2,6-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   2,2′-(methylazanediyl)bis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide)    tris(2,2,2-trifluoroacetate);-   5-amino-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)isophthalamide    tris(2,2,2-trifluoroacetate);-   2,2′-oxybis(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);-   5-bromo-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)isophthalamide    bis(2,2,2-trifluoroacetate);-   N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2-hydroxymalonamide    bis(2,2,2-trifluoro acetate);-   N1,N2-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxalamide;-   N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;-   3,5-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethylcarbamoyl)benzenesulfonic    acid;-   N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-5-hydroxyisophthalamide;-   (2R,3R)—N1,N4-bis(3-((3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)propyl)(methyl)amino)propyl)-2,3-dihydroxysuccinamide;-   2,2′-oxybis(N-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);-   N1,N3-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;-   N1,N2-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxalamide;-   2,2′-oxybis(N-(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);-   N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;-   N1,N4-bis(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;-   2,2′-oxybis(N-(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);-   (S or    R)—N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (S or    R)—N,N′-(2,2′-(2,2′-(2,2′-(1,4-phenylenebis(azanediyl))bis(oxomethylene)bis    (azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(butane-1,4-diyl)bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)acetamido)acetamido)acetamide);-   N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N,N′-(2,2′-(2,2′-(2,2′-(1,4-phenylenebis(methylene))bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (2R,3R)—N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N,N′-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(1,1′-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (2R,3R)—N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)-3,6,9,12,15,18-hexaoxaicosyl)-2,3-dihydroxysuccinamide;-   (E)-3-(4-(4-(N-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide;-   (2R,3R)—N1,N4-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   2,2′,2″-nitrilotris(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);-   N-(32-amino-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide;-   N1,N3,N5-tris(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3,5-tricarboxamide;-   N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide;-   N1,N31-bis(32-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide;-   2R,3R)—N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3-disulfonamide;-   N4,N4′-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)biphenyl-4,4′-disulfonamide;-   (14R,15R)-1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)-14,15-dihydroxy-13-oxo-3,6,9-trioxa-12-azahexadecan-16-oic    acid;-   (2S,3S)—N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(3-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(3-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(4-((R or    S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)isophthalamide;-   (2R,3S)—N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)phthalamide;-   N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide;-   N,N′-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecane-1,19-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide;-   N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide;-   N,N′-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecane-1,19-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(2,2′-(2,2′-(2,2′-(1,4-phenylenebis(azanediyl))bis(oxomethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   Phenylenebis(azanediyl))bis(oxomethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide;-   (2S,3S)—N1,N4-bis(2-(2-(2-(2-(3-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   (2R,3R)—N1,N4-bis(2-(2-(2-(2-(3-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   (2S,3S)—N1,N4-bis(2-(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   (2R,3R)—N1,N4-bis(2-(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;-   (S or    R)—N,N′-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(3-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (S or    R)—N,N′-(1,1′-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N1,N4-bis(2-(2-(2-(2-(4-((S or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-terephthalamide;-   N1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;-   N,N′-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   N,N′-(1,1′-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (S or    R)—N,N′-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);-   (S or    R)—N,N′-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(4-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);    or-   (S or    R)—N,N′-(1,1′-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(4-((S    or    R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide).

In an embodiment, the NHE inhibitor is:

In some embodiments, the compound has the following structure of Formula(I-H):

-   -   or a stereoisomer, prodrug or pharmaceutically acceptable salt        thereof,    -   wherein:    -   (a) n is an integer of 2 or more;    -   (b) Core is a Core moiety having two or more sites thereon for        attachment to two or more NHE-binding small molecule moieties;    -   (c) L is a bond or linker connecting the Core moiety to the two        or more NHE-binding small molecule moieties; and    -   (d) NHE is a NHE-binding small molecule moiety having the        following structure of Formula (XI-H):

wherein:

-   -   B is selected from the group consisting of aryl and        heterocyclyl;    -   each R₅ is independently selected from the group consisting of        hydrogen, halogen, optionally substituted C₁₋₄alkyl, optionally        substituted C₁₋₄alkoxy, optionally substituted C₁₋₄thioalkyl,        optionally substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted aryl, optionally        substituted heteroaryl, hydroxyl, oxo, cyano, nitro, —NR₇R₈,        —NR₇C(═O)R₈, —NR₇C(═O)OR₈, —NR₇C(═O)NR₈R₉, —NR₇SO₂R₈,        —NR₇S(O)₂NR₈R₉, —C(═O)OR₇, —C(═O)R₇, —C(═O)NR₇R₈, —S(O)₁₋₂R₇,        and —SO₂NR₇R₈, wherein R₇, R₈, and R₉ are independently selected        from the group consisting of hydrogen, C₁₋₄alkyl, or a bond        linking the NHE-binding small molecule moiety to L, provided at        least one is a bond linking the NHE-binding small molecule        moiety to L;    -   R₃ and R₄ are independently selected from the group consisting        of hydrogen, optionally substituted C₁₋₄alkyl, optionally        substituted cycloalkyl, optionally substituted cycloalkylalkyl,        optionally substituted aryl, optionally substituted aralkyl,        optionally substituted heterocyclyl and optionally substituted        heteroaryl; or    -   R₃ and R₄ form together with the nitrogen to which they are        bonded an optionally substituted 4-8 membered heterocyclyl; and    -   each R₁ is independently selected from the group consisting of        hydrogen, halogen, optionally substituted C₁₋₆alkyl and        optionally substituted C₁₋₆alkoxy. In some embodiments, n is 2.        In certain embodiments, L is a polyalkylene glycol linker. In        certain embodiments, L is a polyethylene glycol linker.

In certain embodiments, the Core has the following structure:

-   -   wherein:    -   X is selected from the group consisting of a bond, —O—, —NH—,        —S—, C₁₋₆alkylene, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —SO₂NH—,        and —NHSO₂—;    -   Y is selected from the group consisting of a bond, optionally        substituted C₁₋₈alkylene, optionally substituted aryl,        optionally substituted heteroaryl, a polyethylene glycol linker,        —(CH₂)₁₋₆O(CH₂)₁₋₆— and —(CH₂)₁₋₆NY₁(CH₂)₁₋₆—; and    -   Y₁ is selected from the group consisting of hydrogen, optionally        substituted C₁₋₈alkyl, optionally substituted aryl or optionally        substituted heteroaryl.

In some embodiments, the Core is selected from the group consisting of

In certain embodiments, the NHE-binding small molecule moiety has thefollowing structure of Formula (XII-H):

wherein:

-   -   each R₃ and R₄ are independently selected from the group        consisting of hydrogen and optionally substituted C₁₋₄alkyl, or        R₃ and R₄, taken together with the nitrogen to which they are        bonded, form an optionally substituted 4-8 membered        heterocyclyl;    -   each R₁ is independently selected from the group consisting of        hydrogen, halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl; and    -   R₅ is selected from the group consisting of —SO₂—NR₇— and        —NHC(═O)NH—, wherein R₇ is hydrogen or C₁₋₄alkyl.

In some embodiments, R₃ and R₄, taken together with the nitrogen towhich they are bonded, form an optionally substituted 5 or 6 memberedheterocyclyl. In certain embodiments, the optionally substituted 5 or 6membered heterocyclyl is pyrrolidinyl or piperidinyl. In certainembodiments, the optionally substituted 5 or 6 membered heterocyclyl ispyrrolidinyl or piperidinyl, each substituted with at least one amino orhydroxyl. In some embodiments, R₃ and R₄ are independently C₁₋₄alkyl. Incertain embodiments, R₃ and R₄ are methyl. In some embodiments, each R₁is independently selected from the group consisting of hydrogen orhalogen. In certain embodiments, each R₁ is independently selected fromthe group consisting of hydrogen, F and Cl.

In certain embodiments, the compound has the following structure ofFormula (I-I):

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein:

-   -   (a) NHE is a NHE-binding small molecule moiety having the        following structure of Formula (A-I):

wherein:

-   -   each R₁, R₂, R₃, R₅ and R₉ are independently selected from H,        halogen, —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈,        —OR₇, —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇        and R₈ are independently selected from H, C₁₋₆alkyl,        —C₁₋₆alkyl-OH or a bond linking the NHE-binding small molecule        to L, provided at least one is a bond linking the NHE-binding        small molecule to L;    -   R₄ is selected from H, C₁-C₇ alkyl, or a bond linking the        NHE-binding small molecule to L;    -   R₆ is absent or selected from H and C₁-C₇ alkyl; and    -   Ar1 and Ar2 independently represent an aromatic ring or a        heteroaromatic ring;    -   (b) Core is a Core moiety having the following structure of        Formula (B-I):

wherein:

-   -   X is selected from C(X₁), N and N(C₁₋₆alkyl);    -   X₁ is selected from hydrogen, optionally substituted alkyl,        —NX_(a)X_(b), —NO₂, —NX_(c)—C(═O)—NX_(c)—X_(a),        —C(═O)NX_(c)—X_(a), —NX_(c)—C(═O)—X_(a), —NX_(c)—SO₂—X_(a),        —C(═O)—X_(a) and —OX_(a),    -   each X_(a) and X_(b) are independently selected from hydrogen,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted heterocyclylalkyl,        optionally substituted aryl, optionally substituted aralkyl,        optionally substituted heteroaryl and optionally substituted        heteroarylalkyl;    -   Y is C₁₋₆alkylene;    -   Z is selected from —NZ_(a)—C(═O)—NZ_(a)—, —C(═O)NZ_(a)—,        —NZ_(a)—C(═O)— and heteroaryl when X is CX₁;    -   Z is selected from —NZ_(a)—C(═O)—NZ_(a)—, —NZ_(a)—C(═O)— and        heteroaryl when X is N or N(C₁₋₆alkyl); and    -   each X_(c) and Z_(a) is independently selected from hydrogen and        C₁₋₆alkyl; and    -   (c) L is a bond or linker connecting the Core moiety to the        NHE-binding small molecule moieties.

In some embodiments, the NHE-binding small molecule moiety has thefollowing structure:

wherein:

-   -   each R₁, R₂ and R₃ are independently selected from H, halogen,        —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈, —OR₇,        —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇ and R₈        are independently selected from H, C₁₋₆alkyl, —C₁₋₆alkyl-OH or a        bond linking the NHE-binding small molecule to L, provided at        least one is a bond linking the NHE-binding small molecule to L.

In some embodiments, the NHE-binding small molecule moiety has one ofthe following structures:

In some embodiments, L is a polyalkylene glycol linker. In certainembodiments, L is a polyethylene glycol linker. In some embodiments, Xis C(X₁). In some embodiments, each X, is hydrogen. In certainembodiments, X is N. In certain embodiments, each Z_(a) is hydrogen.

In some embodiments, the compound has the structure of Formula (II):

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein:

-   -   (a) NHE is a NHE-binding small molecule moiety having the        structure of Formula (A-I):

wherein:

-   -   each R₁, R₂, R₃, R₅ and R₉ are independently selected from H,        halogen, —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈,        —OR₇, —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇        and R₈ are independently selected from H, C₁₋₆alkyl,        —C₁₋₆alkyl-OH or a bond linking the NHE-binding small molecule        to L, provided at least one is a bond linking the NHE-binding        small molecule to L;    -   R₄ is selected from H, C₁-C₇ alkyl, or a bond linking the        NHE-binding small molecule to L;    -   R₆ is absent or selected from H and C₁-C₇ alkyl; and    -   Ar1 and Ar2 independently represent an aromatic ring or a        heteroaromatic ring;    -   (b) Core is a Core moiety having the following structure of        Formula (C-I):

-   -   wherein:    -   W is selected from alkylene, polyalkylene glycol,        —C(═O)—NH-(alkylene)-NH—C(═O)—, —C(═O)—NH-(polyalkylene        glycol)-NH—C(═O)—, —C(═O)-(alkylene)-C(═O)—,        —C(═O)-(polyalkylene glycol)-C(═O)— and cycloalkyl,    -   X is N;    -   Y is C₁₋₆alkylene;    -   Z is selected from —NZ_(a)—C(═O)—NZ_(a)—, —C(═O)NZ_(a)—,        —NZ_(a)—C(═O)— and heteroaryl;    -   each Z_(a) is independently selected from hydrogen and        C₁₋₆alkyl; and    -   (c) L is a bond or linker connecting the Core moiety to the        NHE-binding small molecules.

In certain embodiments, the NHE-binding small molecule moiety has thefollowing structure:

wherein:

-   -   each R₁, R₂ and R₃ are independently selected from H, halogen,        —NR₇(CO)R₈, —(CO)NR₇R₈, —SO₂—NR₇R₈, —NR₇SO₂R₈, —NR₇R₈, —OR₇,        —SR₇, —O(CO)NR₇R₈, —NR₇(CO)OR₈, and —NR₇SO₂NR₈, where R₇ and R₈        are independently selected from H, C₁₋₆alkyl, —C₁₋₆alkyl-OH or a        bond linking the NHE-binding small molecule to L, provided at        least one is a bond linking the NHE-binding small molecule to L.

In certain embodiments, the NHE-binding small molecule moiety has one ofthe following structures:

In another embodiment, the NHE inhibitor is:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,isomers, and tautomers thereof,

-   -   wherein:    -   Linker is —(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—Z—R¹³—(CH₂)_(t)—Z—;    -   W is independently, at each occurrence, S(O)₂, C(O), or        —(CH₂)_(m)—;    -   Z is independently, at each occurrence, a bond, C(O), or        —C(O)NH—;    -   Y is independently, at each occurrence, O, S, NH, N(C₁-C₃alkyl),        or —C(O)NH—;    -   Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH₃)—, or        —NHC(O)NH—(CHR¹³); m is an integer from 1 to 2; n is an integer        from 1 to 4;    -   r and p are independently, at each occurrence, integers from 0        to 8;    -   s is an integer from 0 to 4;    -   t is an integer from 0 to 4;    -   u is an integer from 0 to 2;    -   R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,        C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,        aryl, heteroaryl containing 1-5 heteroatoms selected from the        group consisting of N, S, P and O, wherein each alkyl, alkenyl,        cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or        heteroaryl is optionally substituted with one or more halogen,        OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—,        —S(O)₂R₉, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹,        —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹, C₁-C₆alkyl, C₂-C₆alkenyl,        C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,        heterocycle, aryl, or heteroaryl; or    -   R¹ and R² together with the nitrogen to which they are attached        can form a heterocyclyl or heteroaryl containing 1-5 heteroatoms        selected from the group consisting of N, S, P and O, wherein the        heterocyclyl or heteroaryl group is optionally substituted with        one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹,        —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R₉, —C(O)R⁹, —C(O)OR⁹,        —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R¹⁰,        C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,        C₃-C₈cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl;    -   R³ and R⁴ are independently halogen, OH, CN, C₁-C₆alkyl,        C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰;    -   R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH. CN, —NO₂,        C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,        C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P and O,        —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R₉, —C(O)R⁹,        —C(O)OR⁹, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹;    -   R⁹ and R¹⁰ are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,        C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,        aryl, or heteroaryl containing 1-5 heteroatoms selected from the        group consisting of N, S, P and O    -   X is a bond, H, N, O, CR¹¹R¹², CR¹¹, C, —NHC(O)NH—, or        C₃-C₆cyclolakyl;    -   R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or        NO₂;    -   R¹³ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,        C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or        heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl,        aryl, or heteroaryl is optionally substituted with one or more        R₁₉;    -   R¹⁴ is independently, at each occurrence, H, C₁-C₆alkyl, or        C₁-C₆haloalkyl; or    -   R⁶ and R¹⁴ together with the atoms to which they are attached        may combine to form, independently, at each occurrence, 5- to-6        membered heterocyclyl, wherein each C₃-C₈ cycloalkyl, or        heterocyclyl is optionally substituted with one or more R¹⁹; or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        may combine to form independently, at each occurrence, C₃-C₈        cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P and O,        wherein each heterocyclyl or heteroaryl is optionally        substituted with one or more R₁₉;    -   R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, at each occurrence, H,        OH, NH₂, or C₁-C₃ alkyl, wherein the alkyl is optionally        substituted with one or more R¹⁹; and    -   R₁₉ are independently, at each occurrence, H, OH, NH₂, oxo,        C₁-C₆alkyl, C₁-C₆Hhaloalkyl, C₁-C₆alkoxy.

In an embodiment, the NHE3 inhibitor is a compound according to theforegoing formula provided that:

-   -   (1) when X is H, n is 1;    -   (2) when X is a bond, O, or CR¹¹R¹², n is 2;    -   (3) when n is 3, X is CR¹¹ or N;    -   (4) when n is 4 X is C;    -   (5) only one of Q or X is —NHC(O)NH— at the time,    -   (6) R¹ and R² together with the nitrogen to which they are        attached, cannot form a pyrrolidinyl;    -   (7) when R¹ and R² are methyl, R³ and R⁴ are halogen, and R⁵ and        R⁸ are H, Linker is not

-   -   (8) when R¹ and R² together with the nitrogen to which they are        attached form a piperidinyl, R³ and R⁴ are halogen, and R⁵ and        R⁸ are H, Linker is not

or

-   -   (9) when R¹ and R², together with the nitrogen to which they are        attached, form 3-aminopiperidin-1-yl, R³ and R⁴ are halogen, and        R⁵, R⁶, R⁷, and R⁸ are H, Linker is not

In an embodiment, the NHE3 compound has a structure according to thefollowing formula:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,isomers, and tautomers thereof, wherein:

-   -   Linker is —(CHR⁸)_(p)—[Y—(CH₂)_(r)]_(s)—Z—R⁸—(CH₂)_(t)—Z—;    -   Q is a bond or —NHC(O)NH—;    -   Z is independently, at each occurrence, a bond, C(O), or        —C(O)NH—;    -   Y is independently, at each occurrence, O, S, NH, N(C₁-C₃alkyl),        or —C(O)NH—;    -   X is a bond, N, O, CR¹¹R¹², CR¹¹, C, or —NHC(O)NH—;    -   n is an integer from 2 to 4;    -   r and p are independently, at each occurrence, integers from 0        to 8;    -   s is an integer from 0 to 4;    -   t is an integer from 0 to 4;    -   u is an integer from 0 to 2;    -   R¹ and R² are independently halogen, OH, CN, C₁-C₆alkyl,        C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰;    -   R³, R⁴, R⁵, and R⁶ are independently H, halogen, OH. CN, —NO₂,        C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,        C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5        heteroatoms selected from the group consisting of N, S, P and O,        —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R₉, —C(O)R⁹,        —C(O)OR⁹, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹;    -   R⁷ is independently, at each occurrence, H, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R⁸ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,        C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or        heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl,        aryl, or heteroaryl is optionally substituted with one or more        R¹⁷; or    -   R⁷ and R⁸ together with the atoms to which they are attached may        combine to form independently, at each occurrence, heterocyclyl        or heteroaryl containing 1-5 heteroatoms selected from the group        consisting of N, S, P and O, wherein each heterocyclyl or        heteroaryl is optionally substituted with one or more R¹⁷;    -   R⁹ and R¹⁰ are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,        C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,        aryl, or heteroaryl containing 1-5 heteroatoms selected from the        group consisting of N, S, P and O;    -   R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or        NO₂;    -   R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently, at each occurrence, H,        OH, NH₂, or C₁-C₃ alkyl, wherein the alkyl is optionally        substituted with one or more R¹⁷; and    -   R¹⁷ is independently, at each occurrence, H, OH, NH₂, oxo,        C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆alkoxy.

In an embodiment, the NHE3 inhibitor compound has a structure accordingto the foregoing formula provided that:

-   -   (1) when X is a bond, O, or CR¹¹R¹², n is 2;    -   (2) when n is 3, X is CR¹¹ or N;    -   (3) when n is 4 X is C;    -   (4) only one of Q or X is —NHC(O)NH— at the time;    -   (5) when R¹ and R² are chloro, Q is —NHC(O)NH—, and R³, R⁴, R⁵,        and R⁶ are H, Linker is not

or

-   -   (6) when R¹ and R² are chloro, Q is —NHC(O)NH—, and R³, R⁴, R⁵,        and R⁶ are H, Linker is not

In an embodiment, the NHE3 inhibitor compound has a structure accordingto the following formula:

-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide);-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide;-   N,N′-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3S,3′S)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];-   N,N′-[(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   1,1′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)formamide];-   1,1′-[(3R,3′R)-(7,14-Dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)formamide];-   1,1′-(5,12-Dioxo-4,6,11,13-tetraazahexadecane-1,16-diyl)bis[N-([3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)piperidine-4-carboxamide];-   1,1′-(5,12-Dioxo-4,6,11,13-tetraazahexadecane-1,16-diyl)bis[N-([3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)piperidine-3-carboxamide];-   N¹,N¹⁸-Bis([3-(6,8-Dichloro-2-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;-   N,N′-[(3S,3′S)-(6,13-Dioxo-5,7,12,14-tetraazaoctadecanedioyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N′-[(3S,3′S)-(6,13-Dioxo-5,7,12,14-tetraazaoctadecanedioyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   1-[2-(2-[(1-[(3-[(S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)oxy]ethoxy)ethyl]-3-[4-(3-[2-(2-[(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)oxy]ethoxy)ethyl]ureido)butyl]urea;-   1-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)-3-(4-(3-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)ureido)butyl)urea;-   1-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]pyrrolidin-3-yl]oxy)ethoxy]ethyl)-3-(4-[3-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]pyrrolidin-3-yl]oxy)ethoxy]ethyl)ureido]butyl)urea;-   3-[(S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]-N-[(3R,28R)-28-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonamido]-2,29-dimethyl-12,19-dioxo-5,8,23,26-tetraoxa-11,13,18,20-tetraazatriacontan-3-yl]benzenesulfonamide;-   N,N-(10-Oxo-3,6,14,17-tetraoxa-9,11-diazanonadecane-1,19-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N,N-[(3S,3′S)-(7-Oxo-3,11-dioxa-6,8-diazatridecane-1,13-diyl]bis[pyrrolidine-1,3-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];-   N¹,N¹⁸-Bis(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamid;-   N¹,N¹⁸-Bis(1-[(3-[(S)-6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;    or-   N¹,N¹⁸-Bis(1-[(3-[(S)-6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide.

In one embodiment of the invention, the NHE3 inhibitor is a compoundaccording to the formula:

In one embodiment of the invention, the NHE3 inhibitor is a compoundaccording to the formula:

In an embodiment the NHE3 inhibitor is one of the following compounds:

-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro,-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]    ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]    ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)-butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)    butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)    ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]    amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)    butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)    ethyl] carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]-amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl    benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea    dihydrochloride;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]    ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]-amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)-sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]    amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfon    amido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]    pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]    pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonyl]    pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]-amino)butyl]urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]    methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]    pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]-amino)butyl]urea;-   3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]-amino)butyl]urea;-   3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]-amino)butyl]urea;-   3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;-   3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;-   3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]    ethyl) carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]    ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)    ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;-   (2R,3S,4R,5S)—N1,N6-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide;-   3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)-butyl]urea;-   3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)-butyl]urea;-   (4R,4aS,8S,8aR)-N4,N8-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl    sulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide;-   (4R,4aS,8S,8aR)-N4,N8-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-amino    piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide;-   3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]octyl]-carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]octyl]-carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]    ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]    ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]    nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;-   4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethyl    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   hydrochloride;-   1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)    ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)-sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;    hydrochloride;-   1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]    amino)butyl]urea;-   4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]-butyl)urea;-   1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]-amino]butyl)urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]    benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)-sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea;-   1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;    hydrochloride;-   3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)-urea    dihydrochloride;-   3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]-amino]butyl)urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;    hydrochloride;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]    amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   4-([(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide;-   4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-3-yl]benzenesulfonamide;-   N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;-   N1,N14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;-   N1,N18-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   -([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide;-   N1,N18-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;-   N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]-heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]-heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)-ethoxy]ethoxy)ethyl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide;-   4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide;-   4-(3-[4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   1,1′-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea];-   1,1′-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea];-   N,N′-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];-   N,N′-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;-   N1,N14-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   N1,N14-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;-   1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea);    and-   1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea).

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. For example, the synthesis ofnon-exemplified compounds may be successfully performed by modificationsapparent to those skilled in the art, e.g., by appropriately protectinginterfering groups, by utilizing other suitable reagents known in theart other than those described, and/or by making routine modificationsof reaction conditions. Alternatively, other reactions disclosed hereinor known in the art will be recognized as having applicability forpreparing other compounds described herein.

Example 1(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-9)

Synthesis of(4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydropicene-3-carboxylic acid (1-2). Into a 1-L pressure tank reactor (10atm) purged and maintained with an inert atmosphere of CO, was placedbenzyl(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylate (preparedaccording to the method described in US Patent 20160151387) (11 g, 15.92mmol, 1.00 equiv.), Pd(PPh₃)₄ (4 g, 3.46 mmol, 0.20 equiv.), THE (250mL), and water (150 mL). The resulting solution was stirred for 2 daysat 50° C. The resulting solution was extracted with 3×150 mL of DCM andthe organic layers combined. The resulting mixture was washed with 3×150mL of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:10). The crude product (20 mL) waspurified by Flash-Prep-HPLC with the following conditions(CombiFlash-1): Column, C₁₈ silica gel; mobile phase, ACN:water=100:0;Detector, UV 254 nm. 1 L product was obtained. This resulted in 6.5 g(69.6%) of 1-2 as a light yellow solid.

Synthesis of 2-Benzyl 10-((2-(trimethylsilyl)ethoxy)methyl)(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2,10-dicarboxylate (1-3). Into a 250-mLround-bottom flask, was placed 1-2 (3 g, 5.11 mmol, 1.00 equiv.), DMF(30 mL), DMAP (102.4 mg, 0.84 mmol, 0.10 equiv.). This was followed bythe addition of TEA (3 mL, 5.80 equiv.) dropwise with stirring at 0° C.To this was added SEMCl (4.2 mL, 4.80 equiv.) dropwise with stirring at0° C. The resulting solution was stirred for 1.5 h at room temperature.The reaction was then quenched by the addition of 50 mL of aq. K₂CO₃.The resulting solution was diluted with 250 mL of DCM. The resultingmixture was washed with 3×150 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:10). Thisresulted in 3.5 g (95.5%) of 1-3 as a light-yellow oil.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(((2-(trimethylsilyl)ethoxy)methoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-4). Into a 300-mLpressure tank reactor (40 atm) purged and maintained with an inertatmosphere of H₂, was placed 1-3 (6.6 g, 9.20 mmol, 1.00 equiv.),palladium on dried and activated carbon (1.32 g, 0.20 equiv.), acetone(150 mL). The resulting solution was stirred overnight at 50° C. Thesolids were collected by filtration. The resulting mixture wasconcentrated under vacuum. This resulted in 4.2 g (73%) of 1-4 as awhite solid.

Synthesis of 2-Benzyl 10-((2-(trimethylsilyl)ethoxy)methyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (1-5). Into a 250-mLround-bottom flask, was placed 1-4 (5.25 g, 8.35 mmol, 1.00 equiv.), DMF(70 mL), Cs₂CO₃ (4.1 g, 12.58 mmol, 1.50 equiv.), BnBr (2.86 g, 16.72mmol, 2.00 equiv.). The resulting solution was stirred for 2 h at 60° C.The resulting solution was diluted with 250 mL of DCM. The resultingsolution was extracted with 2×100 mL of DCM and the organic layerscombined and dried in an oven under reduced pressure. The resultingresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:10). This resulted in 6 g (99%) of 1-5 as an off-white solid.

Synthesis of(3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carboxylic acid (1-6). Into a 250-mL round-bottom flask,was placed 1-5 (5.6 g, 7.79 mmol, 1.00 equiv.), THE (40 mL). This wasfollowed by the addition of hydrogen chloride (4M, 30 mL). The resultingsolution was stirred for 2 h at 60° C. The pH value of the solution wasadjusted to 3 with sodium bicarbonate (sat.). The resulting solution wasextracted with 3×100 mL of DCM and the organic layers combined. Theresulting mixture was washed with 2×150 mL of Brine. The mixture wasdried over anhydrous sodium sulfate. The crude product (20 mL) waspurified by Flash-Prep-HPLC with the following conditions(CombiFlash-1): Column, C₁₈ silica gel; mobile phase, ACN:water=100:0;Detector, UV 254 nm. 1 L product was obtained. This resulted in 3.1 g(68%, 97% purity) of 1-6 as a white solid. MS (ES, m/z): [M+H]⁺=589.4;¹H-NMR (400 MHz, Chloroform-d): δ 0.76 (s, 4H), 0.91 (s, 5H), 1.01-1.21(m, 12H), 1.24-1.49 (m, 9H), 1.56-1.75 (m, 4H), 1.83 (td, J=13.6, 4.6Hz, 1H), 1.91-2.10 (m, 5H), 2.23 (d, J=8.2 Hz, 1H), 2.37 (s, 1H), 2.86(d, J=13.2 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.23 (d, J=12.4 Hz, 1H),5.57 (s, 1H), 7.30-7.45 (m, 5H).

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(chlorocarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (1-7). Oxalyl chloride (0.144 mL, 1.70 mmol)was added dropwise to 1-6 (0.50 g, 0.85 mmol) and DMF (1 drop) in DCM(50 mL) at room temperature. The mixture was stirred at room temperaturefor 1 hour and then evaporated to dryness. The material was used in thefollowing steps without purification.

Synthesis of 2-Benzyl 10-methyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (1-8). Into a 250-mL round-bottom flask, wasplaced 1-7 (200 mg, 0.33 mmol, 1.00 equiv.), MeOH (20 mL), TEA (0.274mL, 6.00 equiv.). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 198 mg (100%) of 1-8 as a light yellow crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-9). Into a 250-mL round-bottom flask purgedand maintained with an inert atmosphere of H₂, was placed 1-8 (198 mg,0.33 mmol, 1.00 equiv.), MeOH (40 mL), Pd/C (20 mg). The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Thecrude product (200 mg) was purified by Prep-HPLC with the followingconditions: Column, XBridge Prep C18 OBD Column, 190*150 mm Sum; mobilephase, water (10 mmol/L NH₄HCO₃+0.1% NH₃·H₂O) and ACN (50.0% ACN up to62.0% in 7 min); Detector, UV 254/220 nm. 111.8 mg product was obtained.This resulted in 111.8 mg (66%) of 1-9 as a light yellow solid. MS (ES,m/z): [M+H]⁺=513.60; ¹H NMR (400 MHz, Chloroform-d) δ 0.76 (d, J=11.2Hz, 1H), 0.84 (s, 3H), 0.88-0.96 (m, 4H), 0.99-1.08 (m, 4H), 1.18 (s,3H), 1.19-1.28 (m, 7H), 1.31-1.39 (m, 4H), 1.40-1.48 (m, 4H), 1.50-1.59(m, 1H), 1.60-1.72 (m, 3H), 1.79-1.89 (m, 1H), 1.91-2.09 (m, 4H),2.15-2.25 (m, 2H), 2.37 (s, 1H), 2.82 (dt, J=10.4, 3.2 Hz, 1H), 3.65 (s,3H), 5.70 (s, 1H), 9.89 (s, 1H).

Example 2(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylicacid (2-1)

Into a 50-mL round-bottom flask, was placed 1-6 (300 mg, 0.51 mmol, 1.00equiv.), MeOH (30 mL), Pd/C (30 mg, 0.10 equiv.). To the above hydrogen(1 atm) was introduced in. The resulting solution was stirred for 2 h atroom temperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions; mobile phase, water(0.05% TFA) and ACN (60.0% ACN up to 77.0% in 8 min); Detector, UV 254nm. This resulted in 110 mg (43%) of 2-1 as a white solid. MS (ES, m/z):[M+H]⁺=499.25; ¹H-NMR (400 MHz, MeOH-d₄): δ 0.81 (s, 4H), 0.91 (s, 3H),0.93-1.01 (m, 2H), 1.11 (s, 3H), 1.13-1.20 (m, 9H), 1.21-1.31 (m, 1H),1.32-1.54 (m, 9H), 1.63-1.81 (m, 3H), 1.81-2.00 (m, 4H), 2.09-2.26 (m,3H), 2.50 (s, 1H), 2.75 (d, J=13.2 Hz, 1H), 3.34 (s, 2H), 5.59 (s, 1H).

Example 3(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Isopropoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (3-2)

Synthesis of 2-Benzyl 10-isopropyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(3-1). Into a 25-mL round-bottom flask, was placed 1-7 (154 mg, 0.25mmol, 1.00 equiv.), DCM (10 mL), propan-2-ol (46 mg, 0.77 mmol, 3.00equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.05 mL, 1.50equiv.). The resulting solution was stirred for 2 days at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:5). This resulted in 114 mg (71%) 3-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(Isopropoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (3-2). Into a 50-mL round-bottom flask purgedand maintained with an inert atmosphere of H₂, 3-1 (114 mg, 0.18 mmol,1.00 equiv.), THF (10 mL), Pd/C (12 mg). The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The crude product (100mg) was purified by Prep-HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water(0.05% NH₃H₂O) and ACN (41.0% ACN up to 57.0% in 8 min); Detector, uv254 nm. 34.9 mg product was obtained. This resulted in 34.9 mg (36%) of3-2 as a white solid. MS (ES, m/z): [M+H]⁺=541.40; ¹H NMR (400 MHz,Chloroform-d) δ 0.74 (d, J=11.2 Hz, 1H), 0.83-0.94 (m, 7H), 1.01-1.05(m, 4H), 1.13-1.17 (m, 3H), 1.18-1.27 (m, 13H), 1.32-1.52 (m, 9H),1.60-1.70 (m, 3H), 1.78-1.88 (m, 1H), 1.91-2.07 (m, 4H), 2.11-2.21 (m,2H), 2.37 (s, 1H), 2.83 (d, J=13.2 Hz, 1H), 4.97-5.04 (m, 1H), 5.70 (s,1H), 9.9 (s, 1H).

Example 4(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-Hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (4-2)

Synthesis of 2-Benzyl 10-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (4-1).Into a 50-mL round-bottom flask, was placed 1-7 (154 mg, 0.25 mmol, 1.00equiv.), DCM (10 mL), 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol (93 mg,0.51 mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.053mL, 1.50 equiv.). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:5). This resulted in 226 mg (118%) of 4-1 as a white crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-Hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (4-2). Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof H₂, was placed 4-1 (226 mg, 0.30 mmol, 1.00 equiv.), MeOH (10 mL),THF (10 mL), Pd/C (23 mg). The resulting solution was stirred overnightat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The crude product (190 mg) was purifiedby Prep-HPLC with the following conditions: Column, XBridge Shield RP18OBD Column, 5 um, 19*150 mm; mobile phase, water (10 mmol/L NH₄HCO₃+0.1%NH₃·H₂O) and ACN (5.0% ACN up to 55.0% in 1 min, up to 68.0% in 7 min);Detector, UV 254 nm. 80.9 mg product was obtained. This resulted in 80.9mg (41%) of 4-2 as a white solid. MS (ES, m/z): [M+H]⁺=663.30; ¹H NMR(400 MHz, MeOH-d₄) δ 0.82-0.98 (m, 7H), 1.00-1.13 (m, 5H), 1.17-1.30 (m,10H), 1.39-1.61 (m, 9H), 1.65-1.83 (m, 3H), 1.84-2.09 (m, 7H), 2.12-2.28(m, 2H), 2.35 (dd, J=12.8, 3.2 Hz, 1H), 2.53 (s, 1H), 2.81 (dt, J=10.4,3.6 Hz, 1H), 5.62 (s, 1H).

Example 5(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Hydroxyethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (5-2)

Synthesis of 2-Benzyl 10-(2-(benzyloxy)ethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(5-1). Into a 25-mL round-bottom flask, was placed 1-7 (154 mg, 0.25mmol, 1.00 equiv.), DCM (10 mL), 2-(benzyloxy)ethan-1-ol (58 mg, 0.38mmol, 1.50 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.05 mL,1.50 equiv.). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:5). This resulted in 107 mg (58%) of 5-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Hydroxyethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (5-2). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 5-1 (107 mg, 0.15 mmol, 1.00equiv.), MeOH (10 mL), THE (10 mL), Pd/C (20 mg). The resulting solutionwas stirred for 7 days at room temperature. The solids were filteredout. The resulting mixture was concentrated under vacuum. The crudeproduct (100 mg) was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (10 mmol/L NH₄HCO₃+0.1% NH₃·H₂O) and ACN (40.0% ACNup to 70.0% in 8 min); Detector, uv 254 nm. 23.2 mg product wasobtained. This resulted in 23.2 mg (29%) of 5-2 as a white solid. MS(ES, m/z): [M+H]⁺=543.35; ¹H NMR (400 MHz, MeOH-d₄): δ 0.74 (s, 3H),0.77-0.83 (m, 4H), 0.89-0.95 (m, 5H), 1.05-1.09 (m, 9H), 1.13-1.17 (m,1H), 1.26-1.44 (m, 9H), 1.55-1.71 (m, 3H), 1.72-1.81 (m, 2H), 1.82-1.94(m, 2H), 1.96-2.10 (m, 1H), 2.11-2.24 (m, 2H), 2.40 (s, 1H), 2.67 (d,J=13.2 Hz, 1H), 3.63 (t, J=5.0 Hz, 2H), 4.03 (t, J=5.0 Hz, 2H), 5.51 (s,1H).

Example 6(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (6-2)

Synthesis of 2-Benzyl 10-(2,2,2-trifluoroethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(6-1). Into a 25-mL round-bottom flask, was placed 1-7 (154 mg, 0.25mmol, 1.00 equiv.), DCM (10 g, 117.74 mmol, 464.30 equiv.),2,2,2-trifluoroethan-1-ol (51 mg, 0.51 mmol, 2.00 equiv.), DMAP (3 mg,0.02 mmol, 0.10 equiv.), TEA (0.053 mL, 1.50 equiv.). The resultingsolution was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:5). This resulted in 256 mg (150%)of 6-1 as a white crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (6-2). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 6-1 (256 mg, 0.38 mmol, 1.00equiv.), MeOH (10 mL), THE (10 mL), Pd/C (26 mg). The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The resulting mixture was concentrated under vacuum. The crude product(200 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep OBD C18 Column, 19*250 mm, 5 um; mobile phase,water (0.05% TFA) and ACN (82.0% ACN up to 89.0% in 8 min); Detector, UV254 nm. 96.9 mg product was obtained. This resulted in 96.9 mg (44%) of6-2 as a white solid. MS (ES, m/z): [M+H]⁺=581.30; ¹H NMR (400 MHz,MeOH-d₄): δ 0.82-1.00 (m, 7H), 1.01-1.11 (m, 5H), 1.17-1.37 (m, 10H),1.38-1.60 (m, 9H), 1.67-1.81 (m, 3H), 1.82-1.92 (m, 2H), 1.93-2.09 (m,2H), 2.11-2.27 (m, 2H), 2.38 (dd, J=12.8, 3.6 Hz, 1H), 2.54 (s, 1H),2.81 (dt, J=13.5, 3.4 Hz, 1H), 4.50-4.76 (m, 2H), 5.61 (s, 1H).

Example 7(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-Imidazol-1-yl)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (7-2)

Synthesis of 10-(2-(1H-Imidazol-1-yl)ethyl) 2-benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (7-1). Into a 25-mLround-bottom flask, was placed 1-7 (137 mg, 0.23 mmol, 1.00 equiv.), DCM(10 mL), 2-(1H-imidazol-1-yl)ethan-1-ol (51 mg, 0.45 mmol, 2.00 equiv.),DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.047 mL, 1.50 equiv.). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with DCM/MeOH (20:1). This resulted in 140 mg(91%) of 7-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-Imidazol-1-yl)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (7-2). Into a 50-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 7-1 (140 mg, 0.20 mmol, 1.00 equiv.), THE (10 mL), Pd/C (14mg). The resulting solution was stirred overnight at room temperature.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The crude product (120 mg) was purified by Prep-HPLC withthe following conditions: Column, XBridge Prep C18 OBD Column, 19*150 mmSum; mobile phase, water (10 mmol/L NH₄HCO₃+0.1% NH₃·H₂O) and ACN (30.0%ACN up to 66.0% in 7 min); Detector, UV 254/220 nm. 67.4 mg product wasobtained. This resulted in 67.4 mg (55%) of 7-2 as a white solid. MS(ES, m/z): [M+H]⁺=593.40; ¹H NMR (400 MHz, MeOH-d₄): δ 0.69 (s, 3H),0.71-0.75 (m, 4H), 0.80 (s, 3H), 0.84-0.98 (m, 2H), 1.04-1.09 (m, 9H),1.10-1.21 (m, 2H), 1.27-1.30 (m, 3H), 1.31-1.32 (m, 4H), 1.35-1.38 (m,1H), 1.49-1.58 (m, 1H), 1.58-1.69 (m, 2H), 1.70-1.90 (m, 4H), 1.99-2.19(m, 3H), 2.39 (s, 1H), 2.64 (d, J=13.6 Hz, 1H), 4.20-4.33 (m, 4H), 5.49(s, 1H), 6.87 (s, 1H), 7.07 (s, 1H), 7.69 (s, 1H).

Example 8(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholinoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (8-2)

Synthesis of 2-Benzyl 10-(2-morpholinoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(8-1). Into a 25-mL round-bottom flask, was placed 1-7 (137 mg, 0.23mmol, 1.00 equiv.), DCM (10 mL), 2-(morpholin-4-yl)ethan-1-ol (59 mg,0.45 mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.047mL, 1.50 equiv.). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with DCM/MeOH (20:1). Thisresulted in 151 mg (95%) of 8-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholinoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (8-2). Into a 50-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 8-1 (151 mg, 0.22 mmol, 1.00equiv.), THE (10 mL), Pd/C (15 mg). The resulting solution was stirredovernight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The crude product (150mg) was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 19*150 mm 5 um; mobile phase, water (10mmol/L NH₄HCO₃) and ACN (30.0% ACN up to 66.0% in 7 min); Detector, UV254/220 nm. 28.6 mg product was obtained. This resulted in 28.6 mg (22%)of 8-2 as a white solid. MS (ES, m/z): [M+H]⁺=612.70; ¹H NMR (300 MHz,Chloroform-d): δ 0.49-0.98 (m, 8H), 1.02 (s, 4H), 1.09-1.28 (m, 10H),1.29-1.48 (m, 8H), 1.49-1.75 (m, 4H), 1.77-2.12 (m, 5H), 2.20 (d, J=12.9Hz, 2H), 2.37 (s, 1H), 2.44-2.75 (m, 6H), 2.83 (d, J=13.5 Hz, 1H), 3.72(s, 4H), 4.00-4.70 (m, 2H), 5.70 (s, 1H).

Example 9(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (10-2)

Synthesis of 2-Benzyl 10-((R)-quinuclidin-3-yl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(10-1). Into a 25-mL round-bottom flask, was placed 1-7 (154 mg, 0.25mmol, 1.00 equiv.), DCM (10 mL), (3R)-1-azabicyclo[2.2.2]octan-3-ol (65mg, 0.51 mmol, 2.02 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA(0.053 mL, 1.50 equiv.). The resulting solution was stirred overnight atroom temperature. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with DCM/MeOH (10:1).This resulted in 72 mg (41%) of 10-1 as a white crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (10-2). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 10-1 (72 mg, 0.10 mmol, 1.00 equiv.), MeOH (10 mL), THE (10mL), Pd/C (7 mg). The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The crude product (50 mg) was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (40.0%ACN up to 54.0% in 8 min); Detector, UV 254 nm. 11.3 mg product wasobtained. This resulted in 11.3 mg (18%) of 10-2 as a white solid. MS(ES, m/z): [M+H]⁺=608.40; ¹H NMR (400 MHz, MeOH-d₄): δ 0.84-1.93 (m,4H), 0.95 (s, 3H), 0.99-1.12 (m, 5H), 1.16-1.23 (m, 9H), 1.24-1.38 (m,2H), 1.39-1.53 (m, 8H), 1.54-1.65 (m, 1H), 1.68-1.80 (m, 3H), 1.81-2.05(m, 6H), 2.06-2.19 (m, 2H), 2.20-2.29 (m, 2H), 2.31-2.41 (m, 2H), 2.53(s, 1H), 2.82 (dt, J=13.2, 3.4 Hz, 1H), 3.21-3.30 (m, 2H), 3.38-3.44 (m,2H), 3.78 (ddd, J=14.0, 8.7, 2.1 Hz, 1H), 5.12 (dt, J=7.8, 3.5 Hz, 1H),5.61 (s, 1H).

Example 10(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (11-2)

Synthesis of 2-Benzyl 10-(2-(pyridin-2-yl)ethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(11-1). Into a 25-mL round-bottom flask, was placed 1-7 (154 mg, 0.25mmol, 1.00 equiv.), DCM (10 mL), 2-(pyridin-2-yl)ethan-1-ol (63 mg, 0.51mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), TEA (0.053 mL,1.50 equiv.). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:1). This resulted in 217 mg (123%) of 11-1 as a white crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (11-2). Into a 25-mL round-bottomflask, was placed 11-1 (176 mg, 0.25 mmol, 1.00 equiv.), MeOH (10 mL),THE (10 mL), Pd/C (18 mg). The resulting solution was stirred overnightat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The crude product (150 mg) was purifiedby Prep-HPLC with the following conditions: Column, XBridge Shield RP18OBD Column, um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN(40.0% ACN up to 55.0% in 8 min); Detector, UV 254 nm. 35.8 mg productwas obtained. This resulted in 35.8 mg (23%) of 11-2 as a white solid.MS (ES, m/z): [M]⁺=604.35; ¹H NMR (400 MHz, MeOH-d₄): δ 0.77 (s, 3H),0.79-0.90 (m, 7H), 0.91-1.01 (m, 1H), 1.03-1.10 (m, 1H), 1.17 (d, J=14.4Hz, 9H), 1.25-1.33 (m, 1H), 1.37-1.50 (m, 9H), 1.58-1.82 (m, 3H),1.82-2.08 (m, 4H), 2.09-2.30 (m, 3H), 2.49 (s, 1H), 2.75 (dt, J=13.6,3.5 Hz, 1H), 3.39 (t, J=6.2 Hz, 2H), 4.50 (t, J=6.2 Hz, 2H), 5.60 (s,1H), 7.87 (t, J=6.8 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.45 (td, J=8.0,1.6 Hz, 1H), 8.75 (dd, J=6.0, 0.8 Hz, 1H).

Example 11(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Amino-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (12-2)

Synthesis of 10-(2-Amino-2-oxoethyl) 2-benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(12-1). Into a 50-mL round-bottom flask, was placed 1-6 (59 mg, 0.10mmol, 1 equiv.), DMF (5 mL, 0.07 mmol, 0.683 equiv.), TBAI (18 mg, 0.05mmol, 0.486 equiv.), 2-chloroacetamide (11 mg, 0.12 mmol, 1.174 equiv.),K₂CO₃ (17 mg, 0.12 mmol, 1.228 equiv.). The resulting solution wasstirred for 2 hr at 65° C. The resulting solution was diluted with 30 mLof DCM. The resulting mixture was washed with 2×15 mL of brine. Themixture was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with EA. This resulted in 50 mg(77.26%) of 12-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Amino-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (12-2). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 12-1 (200 mg, 0.31 mmol, 1equiv.), MeOH (10 mL, 0.31 mmol, 1.008 equiv.), Pd/C (20 mg, 0.19 mmol,0.607 equiv.). The resulting solution was stirred for 1 hr at roomtemperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (5%Phase B up to 54% in 1 min, up to 68% in 7 min); Detector, uv 254 nm.This resulted in 84.6 mg (49.16%) of 12-2 as a white solid. MS (ES,m/z): [M+H]⁺=556.46; ¹H-NMR (400 MHz, MeOH-d₄): δ 0.82-0.96 (m, 7H),0.99-1.08 (m, 5H), 1.13-1.19 (m, 9H), 1.23 (d, J=3.2 Hz, 1H), 1.40-1.49(m, 8H), 1.55-1.60 (m, 1H), 1.67-1.76 (m, 3H), 1.83-2.00 (m, 4H),2.15-2.19 (m, 2H), 2.35 (d, J=0.4 Hz, 1H), 2.50 (s, 1H), 2.78 (d, J=1.6Hz, 1H), 4.51 (q, J=4.8 Hz, 2H), 5.58 (s, 1H).

Example 12(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((Carboxymethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (13-3)

Synthesis of 2-Benzyl 10-(2-methoxy-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(13-1). Into a 50-mL round-bottom flask, was placed 1-6 (590 mg, 1.00mmol, 1.00 equiv.), Acetone (20 mL), TEA (510 mg, 5.04 mmol, 5.00equiv.), methyl 2-chloroacetate (440 mg, 4.05 mmol, 4.00 equiv.). Theresulting solution was heated to reflux for 4 hr. The resulting mixturewas concentrated under vacuum. The resulting solid was washed with 3×10mL of Hexane. This resulted in 600 mg (91%) of 13-1 as a white solid.

Synthesis of2-(((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)oxy)acetic acid (13-2). Into a 50-mL round-bottomflask, was placed benzyl 13-1 (600 mg, 0.91 mmol, 1.00 equiv.), THF (10mL), water (10 mL), LiOH·H₂O (190 mg, 4.52 mmol, 5.00 equiv.). Theresulting solution was stirred for 3 h at room temperature. Theresulting solution was diluted with 30 mL of water. The pH value of thesolution was adjusted to 2-3 with 1.0 M hydrogen chloride. The resultingsolution was extracted with 3×30 mL of DCM and the organic layerscombined. The resulting mixture was washed with 1×40 mL of water and1×40 mL of sodium chloride sat. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 520 mg(89%) of 13-2 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((Carboxymethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (13-3). Into a 100-mL round-bottom flask, was placed 13-2 (150 mg,0.23 mmol, 1 equiv.), EA (16 mL), Pd/C (4.9 mg, 0.05 mmol, 0.199equiv.). To the above H₂ (g) was introduced in. The resulting solutionwas stirred for 1 overnight at room temperature. The solids werefiltered out. The resulting mixture was concentrated. The crude product(130 mg) was purified by Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19*150 mm Sum; mobile phase, water(0.05% T FA) and ACN (5% Phase B up to 62% in 1 min, up to 76% in 7min); Detector, uv. product was obtained. This resulted in 89.2 mg(69.09%) of 13-3 as a white solid. MS (ES, m/z): [M+H]⁺=557.30; ¹H NMR(400 MHz, MeOH-d₄): δ 0.84 (s, 3H), 0.85-0.89 (m, 1H), 0.93 (s, 3H),0.95-1.09 (m, 2H), 1.10 (s, 3H), 1.17 (t, J=4.5 Hz, 9H), 1.20-1.30 (m,1H), 1.38-1.62 (m, 9H), 1.63-1.79 (m, 3H), 1.80-2.09 (m, 4H), 2.10-2.28(m, 2H), 2.33 (q, J=5.5 Hz, 1H), 2.51 (s, 1H), 2.78 (d, J=13.2 Hz, 1H),4.58 (q, J=13.2 Hz, 2H), 5.58 (s, 1H).

Example 13(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (14-1)

Into a 100-mL round-bottom flask, was placed 13-1 (125 mg, 0.19 mmol, 1equiv.), EA (12 mL), Pd/C (25 mg, 0.23 mmol, 1.242 equiv.). To the aboveH₂ (g) was introduced in. The resulting solution was stirred for 1overnight at room temperature. The solids were filtered out. Theresulting mixture was concentrated. The crude product (100 mg) waspurified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, um, 19*150 mm; mobile phase, water (0.05% TFA) andACN (66% Phase B up to 83% in 8 min); Detector, uv. product wasobtained. This resulted in 127.6 mg (118.20%) of 14-1 as a white solid.MS (ES, m/z): [M+H]⁺=571.30; ¹H NMR (400 MHz, MeOH-d₄) δ: 0.84 (s, 3H),0.85-0.89 (m, 1H), 0.93 (s, 3H), 0.98-1.31 (m, 16H), 1.32-1.59 (m, 9H),1.65-1.79 (m, 3H), 1.80-2.04 (m, 4H), 2.08-2.27 (m, 2H), 2.51 (s, 1H),2.78 (d, J=13.2 Hz, 1H), 3.73 (s, 3H), 4.62 (q, J=14.5 Hz, 2H), 5.58 (s,1H).

Example 14(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-Butoxy)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (15-2)

Synthesis of 2-Benzyl 10-(2-(tert-butoxy)-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (15-1). Into a 100-mLround-bottom flask, was placed 1-6 (295 mg, 0.50 mmol, 1 equiv.), DMF (5mL, 0.07 mmol), TBAI (92 mg, 0.25 mmol, 0.497 equiv.), K₂CO₃ (83 mg,0.60 mmol, 1.199 equiv.), tert-butyl 2-chloroacetate (91 mg, 0.60 mmol,1.206 equiv.). The resulting solution was stirred for 2 hr at 65° C. Theresulting solution was diluted with 50 mL of DCM. The resulting mixturewas washed with 2×15 mL of brine. The mixture was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:3). This resulted in 200 mg (56.79%) of 15-1 asyellow oil.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-Butoxy)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (15-2). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed benzyl 15-1 (200 mg, 0.28 mmol, 1 equiv.), MeOH (10 mL, 0.31mmol), Pd/C (30 mg, 0.28 mmol). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentrated.The crude product was purified by Prep-HPLC with the followingconditions (2 #-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge ShieldRP18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05% TFA) andACN (5% Phase B up to 80% in 1 min, up to 90% in 7 min); Detector, UV254 nm. product was obtained. This resulted in 21 mg (12.04%) of 15-2 asa white solid. MS (ES, m/z): [M+H]⁺=613.40; ¹H-NMR (400 MHz, MeOH-d₄): δ0.72-0.99 (m, 8H), 1.00-1.29 (m, 15H), 1.32-1.59 (m, 17H), 1.63-1.68 (m,4H), 1.91-2.17 (m, 5H), 2.20-2.27 (m, 1H), 2.29 (d, J=1.6 Hz, 1H), 2.38(s, 1H), 2.84 (d, J=1.6 Hz, 1H), 4.47 (q, J=5.6 Hz, 2H), 5.71 (s, 1H).

Example 15(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylic acid (27-2)

Synthesis of 2-Benzyl 10-methyl(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2,10-dicarboxylate(27-1). (Trimethylsilyl)diazomethane in ether (2M) was added dropwise to1-2 (100 mg, 0.170 mmol) in MeOH (3 mL) until yellow color persisted(˜1.2 mmol added). The reaction was stirred at room temperature for 30minutes and then evaporated to provide 27-1 (0.1 g, quantitative) as awhite solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-10-(Methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylicacid (27-2). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of hydrogen (1 atm), was placed 27-1 (100 mg, 0.17mmol, 1.00 equiv.), MeOH (25 mL), Pd/C (20 mg). The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (70.0% ACN up to 82.0% in 7min); Detector, UV 254 nm. This resulted in 25.7 mg (30%) of 27-2 as awhite solid. MS (ES, m/z): [M+H]⁺=511.25; ¹H-NMR (400 MHz, MeOH-d₄,ppm): δ 0.73-0.83 (m, 3H), 0.91-0.97 (m, 1H), 1.03-1.17 (m, 15H),1.18-1.23 (m, 2H), 1.28-1.35 (m, 6H), 1.41-1.52 (m, 2H), 1.53-1.69 (m,3H), 1.71-1.93 (m, 4H), 2.03-2.18 (m, 2H), 2.45 (s, 1H), 3.15-3.21 (m,1H), 3.58 (s, 3H), 5.54 (s, 1H), 6.76 (d, J=2.0 Hz, 1H).

Example 16(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (29-2)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (29-1). Into a 250-mLround-bottom flask, was placed methyl 2-aminoacetate hydrochloride (540mg, 4.30 mmol, 3.00 equiv.), DCM (60 mL), TEA (0.59 mL, 3.00 equiv.), asolution of PH-RDX-013-291-4 (860 mg, 1.42 mmol, 1.00 equiv.) in DCM (30mL). The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 900 mg(96%) of 29-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (29-2). Into a 250-mLround-bottom flask, was placed 29-1 (500 mg, 0.76 mmol, 1.00 equiv.)EtOAc (15 mL), MeOH (15 mL), Pd/C (50 mg). To the above hydrogen (1 atm)was introduced in. The resulting solution was stirred for 1 h at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in 8 mL of THF-MeOH(1:1). The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, Sum, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (52.0% ACN up to 70.0% in 8min); Detector, UV 254 nm. This resulted in 284.1 mg (66%) of 29-2 as awhite solid. MS-PH (ES, m/z): [M+H]⁺=570.30; ¹H NMR (400 MHz, MeOH-d₄,ppm): δ 0.74 (s, 3H), 0.76 (s, 1H), 0.83 (s, 3H), 0.90-0.95 (m, 2H),0.97 (s, 3H), 1.06 (s, 6H), 1.08 (s, 3H), 1.16 (d, J=13.6 Hz, 1H),1.27-1.29 (m, 4H), 1.31 (s, 3H), 1.34-1.38 (m, 2H), 1.56-1.67 (m, 3H),1.77 (d, J=13.6 Hz, 2H), 1.85-1.92 (m, 2H), 1.98-2.06 (m, 2H), 2.11-2.15(m, 1H), 2.40 (s, 1H), 2.67-2.71 (m, 1H), 3.61 (s, 3H), 3.75 (d, J=17.6Hz, 1H), 3.85 (d, J=17.2 Hz, 1H), 5.49 (s, 1H).

Example 17(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (30-3)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-Butoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (30-1). Into a250-mL round-bottom flask, was placed tert-butyl 2-aminoacetatehydrochloride (828 mg, 4.94 mmol, 3.00 equiv.), DCM (80 mL), TEA (0.728mL, 6.00 equiv.), a solution of 1-7 (1.0 g, 1.65 mmol, 1.00 equiv.) inDCM (20 mL). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:1). This resulted in 1.19 g (99%) of 30-1 as a light yellow solid.

Synthesis of((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)glycine (30-2). Into a 100-mL round-bottom flask,was placed 30-1 (1.19 g, 1.70 mmol, 1.00 equiv.), DCM (10 mL),trifluoroacetic acid (10 mL). The resulting solution was stirred for 1 hat room temperature. The resulting mixture was concentrated undervacuum. The resulting mixture was washed with 2×100 mL of n-hexane. Thisresulted in 1.0 g (91%) of 30-2 as an off-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((Carboxymethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (30-3). Into a 100-mL round-bottom flask, was placed 30-2 (560 g,848.62 mmol, 1.00 equiv.), Pd/C (50 mg), THE (30 mL). To the abovehydrogen (1 atm) was introduced in. The resulting solution was stirredfor 1 h at room temperature. The solids were filtered out. The crudeproduct was purified by Prep-HPLC with the following conditions: Column,XBridge Prep OBD C18 Column, 19*250 mm, Sum; mobile phase, water (0.05%TFA) and ACN (45.0% ACN up to 65.0% in 8 min); Detector, UV 254 nm. Thisresulted in 289 mg of 30-3 as a white solid. MS (ES, m/z):[M+H]⁺=556.30; ¹H NMR (300 MHz, MeOH-d₄, ppm): δ 0.87 (s, 3H), 0.90 (s,1H), 0.96 (s, 3H), 1.02 (d, J=14.0 Hz, 2H), 1.10 (s, 3H), 1.19 (s, 3H),1.20 (s, 3H), 1.22 (s, 3H), 1.28 (d, J=14.4 Hz, 1H), 1.40-1.56 (m, 9H),1.67-2.22 (m, 10H), 2.50 (s, 1H), 2.78 (dt, J=13.4 Hz, 3.3 Hz, 1H), 3.82(d, J=17.4 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 5.58 (s, 1H).

Example 18(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)(methyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (31-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (31-1). Intoa 100-mL round-bottom flask, was placed methyl 2-(methylamino)acetatehydrochloride (172 mg, 1.23 mmol, 3.00 equiv.), DCM (15 mL), TEA (0.171mL, 3.00 equiv.), a solution of 1-7 (250 mg, 0.41 mmol, 1.00 equiv.) inDCM (5 mL). The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 0.25 g (90%) of 31-1 as an off-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)(methyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (31-2). Into a 100-mLround-bottom flask, was placed 31-1 (250 mg, 0.37 mmol, 1.00 equiv.),MeOH (15 mL), Pd/C (25 mg). To the above hydrogen (1 atm) was introducedin. The resulting solution was stirred for 1 h at room temperature. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (58.0% ACN up to74.0% in 8 min); Detector, UV 254 nm. This resulted in 28.6 mg (13%) of31-2 as a white solid. MS (ES, m/z): [M+H]⁺=584.35; ¹H NMR (400 MHz,MeOH-d₄, ppm): δ 0.84 (s, 3H), 0.92 (s, 3H), 0.93-0.98 (m, 2H), 1.05 (s,3H), 1.06-1.08 (m, 1H), 1.15 (d, J=4.0 Hz, 3H), 1.17 (s, 3H), 1.19 (d,J=2.4 Hz, 3H), 1.26 (d, J=12.0 Hz, 1H), 1.33-1.43 (m, 5H), 1.45 (s, 3H),1.48-1.49 (m, 1H), 1.69-1.79 (m, 3H), 1.84-1.90 (m, 2H), 1.92-2.03 (m,2H), 2.18-2.21 (m, 2H), 2.54 (s, 1H), 2.74-2.80 (m, 2H), 2.93 (s, 1H),3.19 (s, 2H), 3.70 (s, 3H), 3.98 (d, J=17.2 Hz, 1H), 4.23 (d, J=17.2 Hz,1H), 5.55 (s, 1H).

Example 19(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(Methoxycarbonyl)pyrrolidine-1-carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (33-2)

Synthesis of Methyl((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)-D-prolinate(33-1). Into a 100-mL round-bottom flask, was placed(2R)-pyrrolidine-2-carboxylic acid hydrochloride (245 mg, 1.62 mmol,3.00 equiv.), DCM (15 mL), TEA (0.206 mL, 3.00 equiv.), a solution of1-7 (300 mg, 0.49 mmol, 1.00 equiv.) in DCM (5 mL). The resultingsolution was stirred for 1 h at room temperature. The resulting mixturewas concentrated under vacuum. This resulted in 320 mg (93%) of 33-1 asa white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(Methoxycarbonyl)pyrrolidine-1-carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (33-2). Intoa 100-mL round-bottom flask, was placed 33-1 (320 mg, 0.46 mmol, 1.00equiv.), EtOAc (20 mL), Pd/C (32 mg). To the above hydrogen (1 atm) wasintroduced in. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in 8 mL of MeOH.The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, Sum, 19*150 mm;mobile phase, water (10 mmol/L NH₄HCO₃+0.1% NH₃·H₂O) and ACN (35.0% ACNup to 65.0% in 8 min); Detector, UV 254 nm. This resulted in 26 mg (9%)of 33-2 as a white solid. MS (ES, m/z): [M+H]⁺=610.4; ¹H NMR (400 MHz,MeOH-d₄, ppm): δ 0.86 (s, 3H), 0.93 (s, 1H), 0.97 (s, 3H), 1.00 (s, 3H),1.05-1.09 (m, 2H), 1.17 (s, 3H), 1.18 (s, 3H), 1.21 (s, 3H), 1.27 (d,J=14.3 Hz, 1H), 1.35-1.45 (m, 4H), 1.47 (s, 3H), 1.48-1.51 (m, 2H),1.65-1.87 (m, 3H), 1.90-2.03 (m, 7H), 2.05-2.26 (m, 3H), 2.51-2.55 (m,2H), 2.81 (dt, J=13.4, 3.3 Hz, 1H), 3.71-3.76 (m, 5H), 4.44 (dd, J=8.6,3.8 Hz, 1H), 5.62 (s, 1H).

Example 20(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-Dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (35-2)

Synthesis of Dimethyl ((3 S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)-L-glutamate(35-1). Into a 250-mL round-bottom flask, was placed 1, 5-dimethyl(2S)-2-aminopentanedioate hydrochloride (261 mg, 1.23 mmol, 3.00equiv.), DCM (15 mL), TEA (0.171 mL, 3.00 equiv.), a solution of 1-7(250 mg, 0.41 mmol, 1.00 equiv.) in DCM (5 mL). The resulting solutionwas stirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 250 mg (81%) of 35-1 as anoff-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-Dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (35-2). Into a100-mL round-bottom flask, was placed 35-1 (250 mg, 0.34 mmol, 1.00equiv.), EtOAc (20 g, 226.99 mmol, 677.32 equiv.), Pd/C (30 mg). To theabove hydrogen (1 atm) was introduced in. The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, Sum, 19*150 mm; mobile phase,water (0.05% TFA) and ACN (53.0% ACN up to 71.0% in 8 min); Detector, UV254 nm. This resulted in 33.3 mg (15%) of 35-2 as a white solid. MS (ES,m/z): [M+H]⁺=656.35; ¹H NMR (300 MHz, Chloroform-d, ppm): δ 0.75 (d,J=11.1 Hz, 1H), 0.84 (s, 3H), 0.91 (s, 3H), 0.97 (s, 1H), 1.02 (s, 1H),1.05 (s, 3H), 1.14 (s, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.24-1.30 (m,1H), 1.33-1.49 (m, 9H), 1.59-1.68 (m, 3H), 1.83-2.07 (m, 7H), 2.17-2.22(m, 2H), 2.24-2.49 (m, 3H), 2.86 (d, J=13.5, 1H), 3.68 (s, 3H), 3.75 (s,3H), 4.60-4.64 (m, 1H), 5.71 (s, 1H), 6.28 (d, J=7.5 Hz, 1H).

Example 21(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-Dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid(37-2)

Synthesis of Dimethyl((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)-D-aspartate(37-1). Into a 100-mL round-bottom flask, was placed 1,4-dimethyl(2R)-2-aminobutanedioate hydrochloride (201 mg, 1.02 mmol, 1.00 equiv.),DCM (20 mL), TEA (0.353 mL, 5.00 equiv.). The resulting solution wasstirred 0.5 h at room temperature. Then this was followed by theaddition of a solution of 1-7 (309 mg, 0.51 mmol, 1.00 equiv.) in DCM(10 mL) dropwise with stirring at room temperature. The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. This resulted in 372 mg (100%) of37-1 as a light yellow crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-Dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (37-2). Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof H₂, was placed 37-1 (372 mg, 0.51 mmol, 1.00 equiv.), MeOH (10 mL),THE (10 mL), Pd/C (37 mg). The resulting solution was stirred overnightat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (5.0%ACN up to 56.0% in 1 min, up to 72.0% in 7 min); Detector, UV 254 nm.This resulted in 206 mg (63%) of 37-2 as a white solid. MS (ES, m/z):[M+H]⁺=642; ¹H NMR (400 MHz, MeOH-d₄ ppm): δ 0.84 (s, 4H), 0.91 (s, 3H),0.95-1.00 (m, 5H), 1.13-1.21 (m, 9H), 1.25 (d, J=13.2 Hz, 1H), 1.38-1.52(m, 9H), 1.62-1.81 (m, 3H), 1.82-2.04 (m, 4H), 2.05-2.26 (m, 3H), 2.49(s, 1H), 2.72-2.86 (m, 2H), 2.95 (dd, J=16.4, 5.2 Hz, 1H), 3.65 (s, 3H),3.72 (s, 3H), 4.76 (dd, J=8.0, 5.6 Hz, 1H), 5.58 (s, 1H).

Example 22(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-Methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (39-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (39-1). Into a100-mL round-bottom flask, was placed methyl (2S)-2-aminopropanoatehydrochloride (172 mg, 1.23 mmol, 2.993 equiv.), DCM (15 mL), TEA (0.171mL, 1.23 mmol, 2.988 equiv.), a solution of 1-7 (250 mg, 0.41 mmol, 1equiv.) in DCM (5 mL). The resulting solution was stirred for 1 hr atroom temperature. The resulting mixture was concentrated. This resultedin 250 mg (90.11%) of PH-RDX-013-455-1 as a light yellow solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-Methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (39-2). Into a 100-mLround-bottom flask, was placed 39-1 (250 mg, 0.37 mmol, 1.00 equiv.),MeOH (25 mL), Pd/C (25 mg). To the above hydrogen (1 atm) was introducedin. The resulting solution was stirred for 1 h at room temperature. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (53.0% ACN up to71.0% in 8 min); Detector, UV 254 nm. This resulted in 31.7 mg (15%) of39-2 as a white solid. (ES, m/z): [M+H]⁺=584.35; ¹H NMR (300 MHz,Chloroform-d, ppm): δ 0.77 (d, J=11.7 Hz, 1H), 0.87 (s, 3H), 0.95 (s,3H), 1.09 (s, 3H), 1.17 (s, 3H), 1.22 (s, 3H), 1.26 (s, 3H), 1.29-1.32(m, 1H), 1.32-1.51 (m, 11H), 1.59-1.79 (m, 3H), 1.83-2.07 (m, 9H), 2.19(d, J=10.5, 1H), 2.37 (s, 1H), 2.86 (d, J=13.5 Hz, 1H), 3.75 (s, 3H),4.56-4.66 (m, 1H), 5.71 (s, 1H), 5.95 (d, J=7.2 Hz, 1H).

Example 23(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-Hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (41-2)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-Hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(41-1). Into a 100-mL round-bottom flask, was placed methyl(2S)-2-amino-3-hydroxypropanoate hydrochloride (211 mg, 1.36 mmol, 2.00equiv.), DCM (20 mL), TEA (0.283 mL, 3.00 equiv.). The resultingsolution was stirred for 0.5 h at room temperature. Then this wasfollowed by the addition of a solution of 1-7 (412 mg, 0.68 mmol, 1.00equiv.) in DCM (10 mL) dropwise with stirring at room temperature. Theresulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 468 mg(100%) of 41-1 as a light yellow crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (41-2).Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of H₂, was placed 41-1 (468 mg, 0.68 mmol, 1.00 equiv.), MeOH(20 mL), THF (10 mL), Pd/C (50 mg). The resulting solution was stirredovernight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05% TFA)and ACN (45.0% ACN up to 63.0% in 8 min); Detector, UV 254 nm. Thisresulted in 283 mg (70%) of 41-2 as a white solid. MS (ES, m/z):[M+H]⁺=600.40; ¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.81-0.89 (m, 4H), 0.91(s, 3H), 0.95-1.07 (m, 2H), 1.10 (s, 3H), 1.13-1.20 (m, 9H), 1.20-1.30(m, 1H), 1.40 (s, 3H), 1.43-1.52 (m, 5H), 1.61-1.79 (m, 3H), 1.80-2.08(m, 4H), 2.09-2.29 (m, 3H), 2.50 (s, 1H), 2.78 (dt, J=13.2, 3.2 Hz, 1H),3.34 (s, 1H), 3.72 (s, 3H), 3.78 (dd, J=11.2, 4.8 Hz, 1H), 3.88 (dd,J=11.2, 4.8 Hz, 1H), 4.40-4.57 (m, 1H), 5.58 (s, 1H), 7.87 (d, J=7.7 Hz,1H).

Example 24(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid(44-2)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (44-1).Into a 100-mL round-bottom flask, was placed EDCI (53.4 mg, 0.28 mmol,1.50 equiv.), DCM (15 mL), DMAP (113 mg, 0.92 mmol, 5.00 equiv.). Theresulting solution was stirred for 1 h at room temperature. 30-2 (120mg, 0.19 mmol, 1.00 equiv.) was added. The resulting solution wasallowed to react, with stirring, for an additional 1 h at 55° C.2-(1H-imidazol-1-yl)ethan-1-ol (83 mg, 0.74 mmol, 4.00 equiv.) wasadded. The resulting solution was allowed to react, with stirring, foran additional overnight at 55° C. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withDCM/MeOH (9:1). This resulted in 85 mg (62%) of 44-1 as an off-whitesolid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (44-2). Into a100-mL round-bottom flask, was placed 44-1 (125 mg, 0.17 mmol, 1.00equiv.), MeOH (20 mL), Pd/C (30 mg). To the above hydrogen (1 atm) wasintroduced in. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (32.0% ACN up to50.0% in 8 min); Detector, UV 254 nm. This resulted in 108.9 mg (99%) of44-2 as a white solid. MS (ES, m/z): [M+H]⁺=650.45; ¹H NMR (400 MHz,MeOH-d₄, ppm): δ 0.84 (s, 3H), 0.85 (s, 1H), 0.91 (s, 3H), 0.94-0.99 (m,1H), 1.04 (s, 3H), 1.05-1.07 (m, 1H), 1.15 (s, 3H), 1.17 (s, 3H), 1.19(s, 3H), 1.26 (d, J=13.8 Hz, 1H), 1.37-1.48 (m, 9H), 1.66-1.75 (m, 3H),1.83-2.19 (m, 7H), 2.49 (s, 1H), 2.78 (dt, J=13.4 Hz, 3.3 Hz, 1H),3.87-3.91 (m, 2H), 4.51-4.55 (m, 4H), 5.58 (s, 1H), 7.56 (s, 1H), 7.69(s, 1H), 8.20 (t, J=5.8 Hz, 1H), 8.98 (s, 1H).

Example 25(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-Hydroxyethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (45-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(benzyloxy)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (45-1). Into a100-mL round-bottom flask, was placed EDCI (44 mg, 0.23 mmol, 1.50equiv.), DCM (15 mL), DMAP (95 mg, 0.78 mmol, 5.00 equiv.). Theresulting solution was stirred for 1 h at room temperature. 30-2 (100mg, 0.15 mmol, 1.00 equiv.) was added. The resulting solution wasallowed to react, with stirring, for an additional 1 h at 55° C.2-(benzyloxy)ethan-1-ol (0.088 mL, 4.00 equiv.) was added. The resultingsolution was allowed to react, with stirring, for an additionalovernight at 55° C. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with DCM/MeOH (9:1).This resulted in 95 mg (79%) of 45-1 as an off-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-Hydroxyethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (45-2). Into a100-mL round-bottom flask, was placed 45-1 (120 mg, 0.15 mmol, 1.00equiv.), THE (10 mL), MeOH (10 mL), Pd/C (30 mg). To the above hydrogen(1 atm) was introduced in. The resulting solution was stirred for 2 daysat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (42.0%ACN up to 61.0% in 8 min); Detector, UV 254 nm. This resulted in 58.8 mg(64%) of 45-2 as a white solid. MS (ES, m/z): [M+H]⁺=600.35; ¹H NMR (300MHz, MeOH-d₄ ppm): δ 0.83 (s, 3H), 0.86 (s, 1H), 0.92 (s, 3H), 0.96-1.01(m, 2H), 1.07 (s, 3H), 1.15 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.25(d, J=13.9 Hz, 1H), 1.40-1.52 (m, 9H), 1.71 (t, J=13.4 Hz, 3H),1.81-2.03 (m, 4H), 2.07-2.24 (m, 3H), 2.50 (s, 1H), 2.79 (dt, J=13.2 Hz,3.3 Hz, 1H), 3.71-3.74 (m, 2H), 3.88 (d, J=17.4 Hz, 1H), 3.99 (d, J=17.4Hz, 1H), 4.17-4.20 (m, 2H), 5.58 (s, 1H).

Example 26(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (46-2)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(46-1). Into a 100-mL round-bottom flask, was placed EDCI (53.4 mg, 0.28mmol, 1.50 equiv.), DCM (15 mL), DMAP (226 mg, 1.85 mmol, 10.00 equiv.).The resulting solution was stirred for 1 h at room temperature. 30-2(120 mg, 0.19 mmol, 1.00 equiv.) was added. The resulting solution wasallowed to react, with stirring, for an additional 1 h at 55° C.2-(morpholin-4-yl)ethan-1-ol (0.09 mL, 4.00 equiv.) was added. Theresulting solution was allowed to react, with stirring, for anadditional 2 days at 55° C. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with DCM/MeOH(9:1). This resulted in 125 mg (89%) of 46-1 as an off-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (46-2). Into a 100-mLround-bottom flask, was placed 46-1 (160 mg, 0.21 mmol, 1.00 equiv.),MeOH (15 mL), Pd/C (30 mg). To the above hydrogen was introduced (1 atm)in. The resulting solution was stirred for 1 h at room temperature. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (32.0% ACN up to50.0% in 8 min); Detector, UV 254 nm. This resulted in 77.2 mg (55%) of46-2 as a white solid. MS (ES, m/z): [M+H]⁺=669.45; ¹H NMR (300 MHz,MeOH-d₄, ppm) δ 0.87 (s, 3H), 0.92 (s, 1H), 0.96 (s, 3H), 1.02-1.07 (m,2H), 1.09 (s, 3H), 1.16 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.29 (d,J=14.3 Hz, 1H), 1.40-1.56 (m, 10H), 1.73 (t, J=13.5 Hz, 3H), 1.82-2.10(m, 4H), 2.14-2.29 (m, 3H), 2.50 (s, 1H), 2.80 (dt, J=13.3 Hz, 3.3 Hz,1H), 3.53 (t, J=5.0 Hz, 4H), 3.72-4.20 (m, 6H), 4.53 (q, J=4.6 Hz, 2H),5.58 (s, 1H).

Example 27(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(((pivaloyloxy)methoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (47-2)

Synthesis of 2-Benzyl 10-((pivaloyloxy)methyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate(47-1). Into a 100-mL round-bottom flask, was placed 1-6 (100 mg, 0.17mmol, 1 equiv.), DMF (5 mL, 0.07 mmol), chloromethyl2,2-dimethylpropanoate (30 mg, 0.20 mmol, 1.173 equiv.), TBAI (30 mg,0.08 mmol, 0.478 equiv.), K₂CO₃ (28 mg, 0.20 mmol, 1.193 equiv.). Theresulting solution was stirred for 2 hr at 65° C. The resulting solutionwas diluted with 30 mL of DCM. The resulting mixture was washed with2×15 mL of brine. The mixture was dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentrated.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:3). This resulted in 65 mg (54.45%) of 47-1 as yellow oil.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(((pivaloyloxy)methoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (47-2). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂(1 atm), was placed 47-1 (300 mg, 0.43 mmol, 1 equiv.), MeOH (10 mL,0.31 mmol, 0.733 equiv.), Pd/C (30 mg, 0.662 equiv.). The resultingsolution was stirred for 1 hr at room temperature. The solids werefiltered out. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 5 um,19*150 mm; mobile phase, water (0.05% TFA) and ACN (5% Phase B up to 80%in 1 min, up to 95% in 7 min); Detector, UV 254 nm. This resulted in47.6 mg (18.25%) of 47-2 as a white solid. MS (ES, m/z): [M+H]⁺=613.46;¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.83-0.89 (m, 7H), 1.00-1.06 (m, 5H),1.15-1.19 (m, 18H), 1.22-1.29 (m, 3H), 1.40-1.51 (m, 8H), 1.65-1.68 (m,3H), 1.82-1.98 (m, 3H), 2.14-2.29 (m, 3H), 2.50 (s, 1H), 2.77 (d, J=13.6Hz, 1H), 5.58 (s, 1H), 5.69 (d, J=5.6 Hz, 1H), 5.78 (d, J=5.6 Hz, 1H).

Example 28(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (48-2)

Synthesis of 2-benzyl 10-(((isopropoxycarbonyl)oxy)methyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (48-1). Into a100-mL round-bottom flask, was placed 1-6 (300 mg, 0.51 mmol, 1 equiv.),DMF (5 mg, 0.07 mmol, 0.134 equiv.), chloromethyl propan-2-yl carbonate(93 mg, 0.61 mmol, 1.196 equiv.), K₂CO₃ (84 mg, 0.61 mmol, 1.193equiv.), TBAI (90 mg, 0.24 mmol, 0.478 equiv.). The resulting solutionwas stirred for 2 hr at 65° C. The resulting solution was diluted with50 mL of DCM. The resulting mixture was washed with 2×25 mL of brine.The mixture was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:3). Thisresulted in 200 mg (55.69%) of 48-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (48-2). Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof H₂ (1 atm), was placed 48-1 (300 mg, 0.43 mmol, 1 equiv.), MeOH (10mL, 0.31 mmol, 0.733 equiv.), Pd/C (30 mg, 0.662 equiv.). The resultingsolution was stirred for 1 hr at room temperature. The solids werefiltered out. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 5 um,19*150 mm; mobile phase, water (0.05% TFA) and ACN (5% Phase B up to 74%in 1 min, up to 88% in 7 min); Detector, UV 254 nm. This resulted in148.2 mg (56.64%) of 48-2 as a white solid. MS (ES, m/z): [M+H]⁺=615.40;¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.83-0.89 (m, 7H), 0.97-1.06 (m, 5H),1.13-1.23 (m, 16H), 1.40-1.53 (m, 9H), 1.66-2.03 (m, 7H), 2.11-2.30 (m,3H), 2.50 (s, 1H), 2.77 (d, J=13.2 Hz, 1H), 4.84-4.90 (m, 1H), 5.58 (s,1H), 5.68 (d, J=5.6 Hz, 1H), 5.75 (d, J=5.6 Hz, 1H).

Example 29(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (49-2)

Synthesis of 2-Benzyl 10-(1-((isopropoxycarbonyl)oxy)ethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (49-1). Into a 100-mLround-bottom flask, was placed 1-6 (400 mg, 0.68 mmol, 1.00 equiv.),1-chloroethyl propan-2-yl carbonate (135.8 mg, 0.82 mmol, 1.20 equiv.),TBAI (125 mg, 0.89 mmol, 0.50 equiv.), potassium methaneperoxoate (112mg, 0.80 mmol, 1.20 equiv.), DMF (15 mL). The resulting solution wasstirred for 2 h at room temperature. The resulting solution wasextracted with 3×150 mL of DCM and the organic layers combined. Theresulting mixture was washed with 2×250 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:3). This resulted in 450 mg of mixed stereoisomers. Furtherpurification by prep-SFC, and collection of the faster eluting peakprovided 180 mg of 49-1.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (49-2). Into a100-mL round-bottom flask, was placed 49-1, Pd/C (40 mg), MeOH (20 mL),hydrogen (1 atm) was introduced in. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions: mobile phase, water(0.05% TFA) and ACN (5.0% ACN up to 80.0% in 1 min, up to 90.0% in 7min); Detector, UV 254 nm. This resulted in 87.6 mg (56%) of 49-2. MS(ES, m/z): [M+H]⁺=629.4; ¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.82 (s, 4H),0.91 (s, 3H), 0.96-1.11 (m, 5H), 1.15-1.28 (m, 9H), 1.28-1.36 (m, 7H),1.33-1.58 (m, 12H), 1.71-1.82 (m, 3H), 1.82-2.02 (m, 2H), 2.10-2.25 (m,3H), 2.53 (s, 1H), 2.80 (dt, J=13.6, 3.6 Hz, 1H), 4.89 (d, J=6.4 Hz,1H), 5.60 (s, 1H), 6.73 (q, J=5.4 Hz, 1H).

Example 30(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((Isopropoxycarbonyl)oxy)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (50-2)

Synthesis of 2-Benzyl 10-((R)-1-((isopropoxycarbonyl)oxy)ethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (50-1). Collectionof the slower eluting peak in the purification of 49-1 provided 150 mgof 50-1.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((Isopropoxycarbonyl)oxy)ethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (50-2). Into a 100-mLround-bottom flask, was placed 50-1 (150 mg, 0.21 mmol, 1.00 equiv.),Pd/C (40 mg), MeOH (20 mL), H₂ (1 atm) was introduced in. The resultingsolution was stirred overnight at room temperature. The solids werefiltered out. The crude product was purified by Prep-HPLC with thefollowing conditions; mobile phase, water (0.05% TFA) and ACN (5.0% ACNup to 80.0% in 1 min, up to 90.0% in 7 min); Detector, UV 254 nm. Thisresulted in 79 mg (60%) of 50-2 as a white solid. MS (ES, m/z):[M+H]⁺=629.93; ¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.78-0.93 (m, 7H),0.95-1.15 (m, 5H), 1.15-1.21 (m, 9H), 1.21-1.33 (m, 7H), 1.33-1.56 (m,12H), 1.60-1.80 (m, 3H), 1.83-2.02 (m, 4H), 2.06-2.25 (m, 3H), 2.52 (s,1H), 2.79 (dt, J=13.4, 3.6 Hz, 1H), 4.86 (d, J=1.8 Hz, 1H), 5.60 (s,1H), 6.75 (q, J=5.4 Hz, 1H).

Example 31(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(Diethylamino)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (51-2)

Synthesis of 2-Benzyl 10-(2-(diethylamino)-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (51-1). Intoa 100-mL round-bottom flask, was placed 1-6 (589 mg, 1.00 mmol, 1equiv.), DMF (10 mg, 0.14 mmol), TBAI (185 mg, 0.501 equiv.), K₂CO₃ (165mg, 1.19 mmol, 1.194 equiv.), 2-chloro-N, N-diethylacetamide (180 mg,1.20 mmol, 1.203 equiv.). The resulting solution was stirred for 2 hr at65° C. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:3). This resultedin 600 mg (85.45%) of 51-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(Diethylamino)-2-oxoethoxy)carbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (51-2). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂(1 atm), was placed 51-1 (200 mg, 0.28 mmol, 1 equiv.), MeOH (10 mL,0.31 mmol), Pd/C (30 mg, 0.1 equiv.). The resulting solution was stirredfor 1 overnight at room temperature. The solids were filtered out. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase,water (0.05% TFA) and ACN (5% Phase B up to 66% in 1 min, up to 80% in 7min); Detector, UV 254 nm. This resulted in 91.4 mg (52.43%) of 51-2 asa white solid. MS (ES, m/z): [M+H]⁺=612.55; ¹H NMR (400 MHz, MeOH-d₄,ppm): δ 0.84-0.98 (m, 4H), 0.93-1.01 (m, 3H), 1.04-1.10 (m, 2H),1.10-1.18 (m, 15H), 1.21-1.27 (m, 4H), 1.38-1.48 (m, 8H), 1.57-1.60 (m,1H), 1.61-1.75 (m, 3H), 1.76-2.03 (m, 4H), 2.15-2.19 (m, 2H), 2.34 (d,J=13.2 Hz, 1H), 2.51 (s, 1H), 2.77 (d, J=13.2 Hz, 1H), 3.30-3.40 (m,4H), 4.76 (s, 2H), 5.58 (s, 1H).

Example 32(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholino-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (52-2)

Synthesis of 2-Benzyl 10-(2-morpholino-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (52-1). Into a 100-mLround-bottom flask, was placed 13-2 (150 mg, 0.23 mmol, 1 equiv.), DMF(15 mL), HATU (0.2 g, 0.47 mmol, 2.041 equiv.), morpholine (0.06 mL, 3equiv.), DIPEA (0.08 mL, 0.48 mmol, 2.087 equiv.). The resultingsolution was stirred for 2 hr at room temperature. The resultingsolution was extracted with 500 mL of DCM. The resulting mixture waswashed with 1×500 mL of water. The resulting mixture was washed with1×500 mL of brine. The mixture was dried over anhydrous sodium sulfate.The solids were filtered out. This resulted in 200 mg (120.46%, crude)of 52-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-morpholino-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (52-2). Into a 100-mLround-bottom flask, was placed 52-1 (200 mg, 0.28 mmol, 1 equiv.), EA(16 mL), Pd/C (5.9 mg, 0.06 mmol, 0.198 equiv.). To the above H₂ (g) wasintroduced in. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Prep OBD C18 Column, 19*250 mm,Sum; mobile phase, water (0.05% TFA) and ACN (5% Phase B up to 60% in 2min, up to 75% in 8 min); Detector, UV. This resulted in 56.7 mg(32.43%) of 52-2 as a white solid. MS (ES, m/z): [M+H]⁺=626.45; ¹H NMR(300 MHz, MeOH-d₄, ppm): 0.85 (s, 3H), 0.89-1.00 (m, 4H), 1.02-1.31 (m,15H), 1.33-1.52 (m, 8H), 1.52-1.64 (m, 1H), 1.63-1.80 (m, 3H), 1.81-2.08(m, 4H), 2.09-2.27 (m, 2H), 2.28-2.42 (m, 1H), 2.52 (s, 1H), 2.72-2.88(m, 1H), 3.42-3.61 (m, 4H), 3.62-3.78 (m, 4H), 4.80-4.86 (m, 2H), 5.58(s, 1H).

Example 33(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (53-2)

Synthesis of 2-Benzyl 10-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (53-1). Into a100-mL round-bottom flask, was placed 13-2 (150 mg, 0.23 mmol, 1equiv.), DMF (15 mL), HATU (180 mg, 0.47 mmol, 2.041 equiv.),1-methylpiperazine (0.077 mL, 3 equiv.), DIPEA (0.08 mL, 0.48 mmol,2.087 equiv.). The resulting solution was stirred for 2 hr at roomtemperature. The resulting solution was extracted with 200 mL of DCM.The resulting mixture was washed with 1×200 mL of water. The resultingmixture was washed with 1×200 mL of brine. The mixture was dried overanhydrous sodium sulfate. The solids were filtered out. This resulted in150 mg (88.73%) of 53-1 as a white semi-solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (53-2). Into a100-mL round-bottom flask, was placed 53-1 (150 mg, 0.21 mmol, 1equiv.), EA (16 mL), Pd/C (4.4 mg, 0.201 equiv.). To the above H₂ (g)was introduced in. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Prep OBD C18 Column, 19*250 mm,Sum; mobile phase, water (0.05% TFA) and ACN (41% Phase B up to 59% in 8min); Detector, UV 254 nm. This resulted in 85.8 mg (65.27%) of 53-2 asa white solid. MS (ES, m/z): [M+H]⁺=639.45; ¹H NMR (300 MHz, MeOH-d₄,ppm): 0.79-1.00 (m, 8H), 1.02-1.15 (m, 5H), 1.15-1.22 (m, 9H), 1.23-1.35(m, 2H), 1.36-1.51 (m, 8H), 1.52-1.64 (m, 2H), 1.73 (t, J=13.5 Hz, 3H),1.80-2.27 (m, 7H), 2.32-2.46 (m, 1H), 2.52 (s, 1H), 2.70-2.88 (m, 1H),2.95 (s, 3H), 3.20-3.28 (m, 1H), 3.34-3.47 (m, 2H), 3.52-4.09 (m, 3H),5.58 (s, 1H).

Example 34(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (54-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (54-2). Into a 50-mL round-bottomflask, was placed 54-1 (prepared following the method described inBioorg. Med. Chem. 2010, 18, 433-454)(100 mg, 0.18 mmol, 1.00 equiv.),CH₃CN (5 mL), methyl 2-bromoacetate (55 mg, 0.36 mmol, 2.00 equiv.),potassium carbonate (74 mg, 0.54 mmol, 3.00 equiv.). The resultingsolution was stirred overnight at 60° C. The resulting solution wasextracted with 3×20 mL of EtOAc and the organic layers combined anddried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1/2). The collected fractions were combined and concentrated undervacuum. This resulted in 100 mg (89%) 54-2 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (54-3). Into a 50-mL round-bottom flask, was placed 54-2 (160 mg,0.25 mmol, 1.00 equiv.), Pd/C (80 mg), MeOH (5 mL) under hydrogenatmosphere. The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (30.0% ACN up to48.0% in 8 min); Detector, UV 254 nm. This resulted in 30.7 mg (22%) of54-3 as an off-white solid. MS (ES, m/z): [M+H]⁺=542.45; ¹H NMR (300MHz, DMSO-d6) δ 9.05 (s, 1H), 8.15 (s, 1H), 5.42 (s, 1H), 4.22-3.94 (m,3H), 3.77 (s, 3H), 2.85 (s, 1H), 2.67 (d, J=13.3 Hz, 1H), 2.36 (s, 1H),2.07 (dd, J=11.7, 5.5 Hz, 2H), 1.93-1.49 (m, 7H), 1.35 (s, 8H), 1.11 (d,J=9.4 Hz, 7H), 1.04 (d, J=2.6 Hz, 6H), 0.97 (d, J=13.7 Hz, 2H), 0.85 (s,4H), 0.76 (s, 3H).

Example 35(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (56-2)

Synthesis of Dimethyl2,2′-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)azanediyl)diacetate (56-1). Into a 50-mLround-bottom flask, was placed 54-1 (100 mg, 0.18 mmol, 1.00 equiv.),methyl 2-bromoacetate (273 mg, 1.78 mmol, 10.00 equiv.), ACN (10 mL),potassium carbonate (370 mg, 2.68 mmol, 15.00 equiv.). The resultingsolution was stirred overnight at 60° C. The resulting solution wasextracted with 3×20 mL of EtOAc and the organic layers combined anddried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1/2). The collected fractions were combined and concentrated undervacuum. This resulted in 105 mg (84%) of 56-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-Methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (56-2). Into a 25-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 56-1 (80 mg, 0.11 mmol, 1.00 equiv.), MeOH (5 mL), Pd/C (80mg). The resulting solution was stirred for 2 h at room temperature. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (67.0% ACN up to80.0% in 8 min); Detector, UV 254 nm. This resulted in 36.8 mg (53%) of56-2 as a white solid. MS (ES, m/z): [M+H]⁺=614; ¹H NMR (300 MHz,MeOH-d₄) δ 5.55 (s, 1H), 3.71 (d, J=12.1 Hz, 10H), 2.78 (d, J=13.3 Hz,1H), 2.43 (s, 2H), 2.22-2.05 (m, 2H), 1.91 (s, 1H), 1.82 (d, J=13.7 Hz,4H), 1.70 (d, J=13.3 Hz, 1H), 1.58 (s, 1H), 1.38 (d, J=4.9 Hz, 7H), 1.25(d, J=6.8 Hz, 1H), 1.23-1.07 (m, 10H), 1.02 (d, J=14.5 Hz, 6H), 0.80 (d,J=2.6 Hz, 7H).

Example 362,2′-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-Carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)azanediyl)diacetic acid (57-2)

Synthesis of Dibenzyl2,2′-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)azanediyl)diacetate (57-1). Into a250-mL round-bottom flask, was placed 54-1 (500 mg, 0.89 mmol, 1.00equiv.), CH₃CN (50 mL), potassium carbonate (1.85 g, 13.39 mmol, 15.00equiv.), benzyl 2-bromoacetate (1.42 g, 6.20 mmol, 10.00 equiv.). Theresulting solution was stirred for overnight at 60° C. Add potassiumcarbonate (0.92 g, 7.50 equiv.), benzyl 2-bromoacetate (0.71 mg, 5.00equiv.). The resulting solution was allowed to react, with stirring, foran additional 6 h at 60° C. The resulting mixture was concentrated undervacuum. The residue was dissolved in 100 mL of DCM. The resultingmixture was washed with 1×100 mL of water. The solid was dried in anoven under reduced pressure. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:5). This resulted in 380 mg (50%)of 57-1 as light yellow oil.

Synthesis of2,2′-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-Carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)azanediyl)diacetic acid (57-2). Into a 100-mL round-bottomflask, was placed 57-1 (466 mg, 0.54 mmol, 1.00 equiv.), THE (30 mL),Pd/C (50 mg). To the above hydrogen was introduced in. The resultingsolution was stirred for overnight at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was dissolved in 10 mL of MeOH. The crude product was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18Column, 19*250 mm, Sum; mobile phase, water (0.05% TFA) and ACN (32.0%ACN up to 55.0% in 8 min); Detector, UV 254 nm. This resulted in 263.9mg (83%) of PH-RDX-013-431-0 as a white solid. MS (ES, m/z):[M+H]⁺=586.35; ¹H NMR (300 MHz, MeOH-d₄, ppm): δ 0.87 (s, 3H), 0.95 (s,1H), 1.00 (s, 3H), 1.08 (d, J=13.6 Hz, 1H), 1.15 (s, 3H), 1.17 (s, 3H),1.20 (s, 3H), 1.26 (s, 3H), 1.31-1.39 (m, 2H), 1.38-1.59 (m, 8H),1.65-2.26 (m, 10H), 2.51 (s, 1H), 2.89-2.97 (m, 2H), 3.97 (d, J=3.3 Hz,4H), 5.59 (s, 1H).

Example 37(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Methoxy-2,2-dimethyl-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (58-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (58-1). Into a 25-mLround-bottom flask purged and maintained with an inert atmosphere ofnitrogen, was placed 3-methoxy-2,2-dimethyl-3-oxopropanoic acid (26 mg,0.18 mmol, 1.00 equiv.), DMF (5 mL), 54-1 (100 mg, 0.18 mmol, 1.00equiv.), DIEA (65 mg, 0.50 mmol, 3.00 equiv.), HATU (102 mg, 0.27 mmol,1.50 equiv.). The resulting solution was stirred for 1 h at roomtemperature. The resulting solution was extracted with 3×10 mL of EtOAcand the organic layers combined and dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1/2). The collected fractions werecombined and concentrated under vacuum. This resulted in 110 mg (90%) of58-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (58-2). Into a 50-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 58-1 (50 mg, 0.07 mmol, 1.00 equiv.), MeOH (10 mL), Pd/C (25mg). The resulting solution was stirred for 1 h at room temperature. Thesolids were filtered out. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (60.0% ACN up to78.0% in 8 min); Detector, UV 254 nm. This resulted in 12.3 mg (28%) of58-2 as a white solid. MS (ES, m/z): [M+H]⁺=598; ¹H NMR (300 MHz,MeOH-d₄) δ 0.81-0.98 (m, 12H), 1.06 (d, J=14.2 Hz, 2H), 1.13-1.33 (m,12H), 1.43 (q, J=4.6, 4.1 Hz, 14H), 1.71 (dd, J=27.4, 13.7 Hz, 4H),1.81-1.98 (m, 3H), 2.20 (s, 2H), 2.52 (s, 1H), 2.77 (d, J=13.7 Hz, 1H),3.72 (s, 6H), 5.59 (s, 1H), 7.11 (d, J=9.6 Hz, 1H).

Example 38(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (60-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (60-1). Into a 50-mLround-bottom flask, was placed 54-1 (90 mg, 0.16 mmol, 1 equiv.), DCM (4mL, 0.05 mmol, 0.293 equiv.), DIEA (45.7 mg, 0.35 mmol, 2.2 equiv.).This was followed by the addition of methyl 2-chloro-2-oxoacetate (21.7mg, 0.18 mmol, 1.1 equiv.) dropwise with stirring. The resultingsolution was stirred for 2 hr at room temperature. The resulting mixturewas concentrated under vacuum. This resulted in 110 mg (105.94%) of 60-1as a yellow crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-Methoxy-2-oxoacetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (60-2). Into a 25-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 60-1 (104 mg, 0.16 mmol, 1equiv.), MeOH (5 mg, 0.16 mmol, 0.969 equiv.), Pd/C (50 mg, 0.47 mmol,2.918 equiv.). The resulting solution was stirred for 2.5 hr at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 5 um,19*150 mm; mobile phase, water (0.05% TFA) and ACN (58% Phase B up to72% in 8 min); Detector, UV. This resulted in 45.5 mg (50.84%) of 60-2as a white solid. MS (ES, m/z): [M+H]⁺=555.76; ¹H NMR (300 MHz, DMSO-d6)δ 12.18 (s, 1H), 8.30 (d, J=9.7 Hz, 1H), 5.41 (s, 1H), 3.77 (s, 3H),3.57 (ddd, J=13.2, 9.6, 4.1 Hz, 1H), 2.63 (d, J=13.4 Hz, 1H), 2.41 (s,1H), 2.08 (q, J=9.8, 6.6 Hz, 2H), 1.79 (d, J=13.5 Hz, 3H), 1.69 (d,J=7.0 Hz, 3H), 1.53 (d, J=13.2 Hz, 1H), 1.46-1.16 (m, 9H), 1.17-0.95 (m,13H), 0.81-0.73 (m, 9H).

Example 39(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Methoxy-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (62-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (62-1). Into a 100-mL round-bottomflask, was placed 54-1 (500 mg, 0.89 mmol, 1 equiv.), methyl3-chloro-3-oxopropanoate (243.9 mg, 1.79 mmol, 2 equiv.), TEA (271.1 mg,2.68 mmol, 3 equiv.), CH₂Cl₂ (10 mL, 0.12 mmol, 0.132 equiv.). Theresulting solution was stirred for 1 hr at room temperature. The residuewas applied onto a silica gel column with EtOAc/petroleum ether (1:1).This resulted in 439 mg (74.49%) of 62-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Methoxy-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (62-2). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 62-1 (439 mg, 0.67 mmol, 1equiv.), THE (200 mg, 2.77 mmol, 4.169 equiv.), MeOH (10 mL, 0.31 mmol,0.469 equiv.), Pd/C (10 mL). The resulting solution was stirred for 1 hrat room temperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05% TFA)and ACN (5% Phase B up to 56% in 1 min, up to 70% in 7 min); Detector,UV. This resulted in 61.4 mg (16.20%) of 62-2 as a white solid. MS (ES,m/z): [M+H]⁺=570; ¹H NMR (300 MHz, MeOH-d₄) δ 5.59 (s, 1H), 3.72 (s,4H), 3.35 (s, 2H), 2.77 (dt, J=13.4, 3.7 Hz, 1H), 2.53 (s, 1H), 2.18(ddd, J=19.3, 13.0, 4.5 Hz, 2H), 2.01-1.61 (m, 7H), 1.59-1.34 (m, 9H),1.33-1.13 (m, 11H), 1.07 (d, J=14.9 Hz, 2H), 0.98-0.81 (m, 10H).

Example 40(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-Methoxy-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (64-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (64-1). Into a 25-mL round-bottomflask, was placed 4-methoxy-4-oxobutanoic acid (28 mg, 0.21 mmol, 1.00equiv.), 54-1 (120 mg, 0.21 mmol, 1.00 equiv.), DMF (5 mL), DIEA (78 mg,0.60 mmol, 3.00 equiv.), HATU (122 mg, 0.32 mmol, 1.50 equiv.). Theresulting solution was stirred for 1 h at room temperature. Theresulting solution was extracted with 3×20 mL of EtOAc and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1/2). The collected fractions were combined andconcentrated under vacuum. This resulted in 140 mg (98%) of 64-1 as awhite solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-Methoxy-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (64-2). Into a 50-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 64-1 (50 mg, 0.07 mmol, 1.00equiv.), MeOH (5 mL), Pd/C (25 mg). The resulting solution was stirredfor 1 h at room temperature. The solids were filtered out. The crudeproduct was purified by re-crystallization from ACN. This resulted in39.9 mg (92%) of 64-2 as a white solid. MS (ES, m/z): [M+H]⁺=584; ¹H NMR(300 MHz, MeOH-d₄) δ 0.81-0.96 (m, 10H), 0.99-1.20 (m, 11H), 1.20-1.58(m, 11H), 1.59-1.82 (m, 4H), 1.82-2.08 (m, 3H), 2.08-2.33 (m, 2H),2.42-2.72 (m, 5H), 2.75 (dq, J=12.1, 5.0, 4.2 Hz, 1H), 3.67 (s, 4H),5.65 (s, 1H).

Example 41(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-Methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (66-2)

Synthesis of benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (66-1). Into a 8-mLround-bottom flask, was placed (2E)-4-methoxy-4-oxobut-2-enoic acid(66.48 mg, 0.51 mmol, 1.20 equiv.), 54-1 (200 mg, 0.36 mmol, 1.00equiv.), DIEA (220.13 mg, 1.70 mmol, 4.00 equiv.), DMF (2 mL), HATU (343mg, 0.90 mmol, 1.50 equiv.). The resulting solution was stirred for 1 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (100:1). This resulted in 200 mg (83%) of 66-1 asa yellow solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (66-2). Into a 100-mLround-bottom flask, was placed 66-1 (250 mg, 0.37 mmol, 1.00 equiv.),THE (10 mL), water (5 mL), sodium hydroxide (90 mg, 2.25 mmol, 6.00equiv.), MeOH (10 mL). The resulting solution was stirred for 4 days at60° C. The residue was applied onto a silica gel column withEtOAc/petroleum ether (0-35%). This resulted in 31.8 mg (15%) of 66-2 asa white solid. MS (ES, m/z): [M+H]⁺=582; ¹H NMR (300 MHz, MeOH-d₄) δ8.26 (d, J=9.7 Hz, 1H), 7.08 (d, J=15.4 Hz, 1H), 6.69 (d, J=15.4 Hz,1H), 5.59 (s, 1H), 3.71 (s, 4H), 3.35 (s, 2H), 2.79 (d, J=13.5 Hz, 1H),2.57-2.50 (m, 1H), 2.16 (t, J=12.3 Hz, 2H), 2.04-1.61 (m, 6H), 1.56-1.38(m, 8H), 1.38-1.21 (m, 2H), 1.21-0.80 (m, 20H).

Example 42(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Carboxy-3-methylbutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (68-3)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (68-1). Into a 25-mLround-bottom flask, was placed 54-1 (150 mg, 0.27 mmol, 1 equiv.), DMF(2 mL, 0.03 mmol, 0.102 equiv.), 4-methoxy-3,3-dimethyl-4-oxobutanoicacid (51.5 mg, 0.32 mmol, 1.2 equiv.), DIEA (138.5 mg, 1.07 mmol, 4.0equiv.), HATU (152.8 mg, 0.40 mmol, 1.5 equiv.). The resulting solutionwas stirred for 1 overnight at room temperature. The resulting solutionwas diluted with of EA. The resulting mixture was washed with x ofbrine. The residue was applied onto a silica gel column withEtOAc/petroleum ether. This resulted in 170 mg (90.38%) of 68-1 as anoff-white solid.

Synthesis of4-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)amino)-2,2-dimethyl-4-oxobutanoic acid (68-2). Into a25-mL round-bottom flask, was placed 68-1 (100 mg, 0.14 mmol, 1 equiv.),MeOH (5 mL, 49.40 mmol, 346.760 equiv.), THF (5 mL, 24.69 mmol, 173.289equiv.), H₂O (2 mL, 111.02 mmol, 779.31 equiv.), LiOH·H₂O (54 mg, 1.29mmol, 9.033 equiv.). The resulting solution was stirred for 1 overnightat room temperature. The resulting mixture was concentrated. The pHvalue of the solution was adjusted to 5-6 with HCl. The resultingsolution was extracted with 3×100 mL of EtOAc The residue was appliedonto a silica gel column with DCM/MeOH. This resulted in 80 mg (81.63%)of 68-2 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-Carboxy-3-methylbutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (68-3). Into a 25-mL round-bottom flask purged and maintained withan inert atmosphere of H₂, was placed 68-2 (80 mg, 0.12 mmol, 1 equiv.),MeOH (5 mL, 0.16 mmol, 1.342 equiv.), Pd/C (40 mg, 0.38 mmol, 3.232equiv.). The resulting solution was stirred for 2 hr at roomtemperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water (10 mmol/LNH₄HCO₃+0.1% NH₃·H₂O) and ACN (48% Phase B up to 73% in 8 min);Detector, UV. This resulted in 14.1 mg (20.28%) of 68-3 as a whitesolid. MS (ES, m/z): [M+H]⁺=598; ¹H NMR (300 MHz, MeOH-d₄) δ 5.61 (s,1H), 3.64-3.53 (m, 1H), 2.74 (d, J=13.6 Hz, 1H), 2.51 (s, 3H), 2.28-2.09(m, 2H), 1.91 (dd, J=24.4, 10.9 Hz, 3H), 1.81-1.60 (m, 2H), 1.43 (d,J=10.2 Hz, 8H), 1.24 (d, J=1.8 Hz, 8H), 1.16 (d, J=4.3 Hz, 11H), 1.05(d, J=14.1 Hz, 2H), 0.96-0.81 (m, 11H).

Example 43(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-Methoxy-3,3-dimethyl-4-oxobutanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (69-1)

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of H₂, was placed 68-1 (116 mg, 1 equiv.), MeOH (10 mL), Pd/C(100 mg). The resulting solution was stirred for 2 hr at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Prep C18 OBD Column 19*150 nm 5umC-0013; mobile phase, water (0.05% TFA) and ACN (61% Phase B up to 81%in 8 min); Detector, UV. This resulted in 16.5 mg of 69-1 as a whitesolid. MS (ES, m/z): [M+H]⁺=612; ¹H NMR (300 MHz, MeOH-d₄) δ 5.59 (s,1H), 3.68 (s, 3H), 3.53 (s, 1H), 2.75 (d, J=12.8 Hz, 1H), 2.52 (d, J=5.4Hz, 3H), 2.18 (s, 2H), 1.98-1.81 (m, 3H), 1.70 (dd, J=27.6, 13.7 Hz,4H), 1.43 (d, J=10.0 Hz, 10H), 1.33-1.12 (m, 16H), 1.05 (d, J=13.5 Hz,2H), 0.90-0.80 (m, 9H).

Example 44(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (70-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (70-1). Into a 100-mLround-bottom flask, was placed 54-1 (500 mg, 0.89 mmol, 1 equiv.),methyl 2-(chlorosulfonyl)acetate (308.3 mg, 1.79 mmol, 2 equiv.), TEA(271.1 mg, 2.68 mmol, 3 equiv.), CH₂Cl₂ (15 mL, 235.95 mmol, 264.181equiv.), DMAP (11 mg, 0.09 mmol, 0.101 equiv.). The resulting solutionwas stirred for 1 overnight at room temperature. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:1). This resultedin 250 mg (40.22%) of 70-1 as a yellow solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-Methoxy-2-oxoethyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (70-2). Into a 50-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed MeOH (5 mL), THE (5 mL), Pd/c (100 mg, 0.94 mmol, 1.308equiv.), 70-1 (500 mg, 0.72 mmol, 1 equiv.). The resulting solution wasstirred for 1 hr at room temperature. The solids were filtered out. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, um, 19*150 mm; mobile phase,water (0.05% TFA) and ACN (5% Phase B up to 59% in 1 min, up to 73% in 7min); Detector, UV. This resulted in 44.5 mg (10.22%) of 70-2 as a whitesolid. MS (ES, m/z): [M+H]⁺=606; ¹H NMR (300 MHz, MeOH-d₄) δ 5.59 (s,1H), 4.12 (s, 2H), 3.78 (s, 3H), 3.03 (dd, J=11.6, 5.1 Hz, 1H), 2.76(dt, J=13.5, 3.5 Hz, 1H), 2.51 (s, 1H), 2.28-2.08 (m, 2H), 2.01-1.63 (m,8H), 1.60-1.36 (m, 8H), 1.33-0.99 (m, 15H), 0.83 (d, J=8.6 Hz, 7H).

Example 45(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-Methoxy-3-oxopropyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (72-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-methoxy-3-oxopropyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (72-2). Into a 50-mLround-bottom flask, was placed 54-1 (300 mg, 1 equiv.), DCM (10 mL),methyl 3-(chlorosulfonyl)propanoate (200 mg, 2.0 equiv.), TEA (0.223mL). The resulting solution was stirred overnight at room temperature.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:2). Thisresulted in 326 mg (86%) of 72-2 as a light yellow solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-Methoxy-3-oxopropyl)sulfonamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (72-3). Into a 50-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 72-2 (326 mg, 0.46 mmol, 1.00 equiv.), MeOH (10 mL), THF (10mL), Pd/C (33 mg). The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Prep OBD C18 Column,19*250 mm, 5 um; mobile phase, water (0.05% NH₃·H₂O) and ACN (34.0% ACNup to 50.0% in 9 min); Detector, UV 254 nm. This resulted in 200 mg(70%) of 72-3 as a white solid. MS (ES, m/z): [M+H]⁺=620.70; ¹H NMR (400MHz, MeOH-d₄, ppm): δ 0.78-0.96 (m, 7H), 1.01-1.14 (m, 5H), 1.15-1.24(m, 9H), 1.25-1.33 (m, 1H), 1.38-1.58 (m, 8H), 1.59-2.08 (m, 8H),2.12-2.29 (m, 2H), 2.52 (s, 1H), 2.73-2.90 (m, 3H), 2.98 (dd, J=12.4,4.0 Hz, 1H), 3.35-3.43 (m, 2H), 3.73 (s, 3H), 5.62 (s, 1H).

Example 46(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-Methoxy-2-oxoethoxy)acetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (75-2)

Synthesis of2-(2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)amino)-2-oxoethoxy)aceticacid (74-1). Into a 100-mL round-bottom flask purged and maintained withan inert atmosphere of nitrogen, was placed 54-1 (1.0 g, 1.79 mmol, 1eq.), DMAP (0.1 g, 0.893 mmol, 0.5 eq.), pyridine (10 mL, 0.13 mmol,0.071 eq.). This was followed by the addition of 1,4-dioxane-2,6-dione(228 mg, 1.96 mmol, 1.100 eq.) dropwise with stirring at 0 degrees inice bath. The resulting solution was stirred for 12 hr at 110 degrees C.in an oil bath. The resulting mixture was concentrated under vacuum. Theresulting residue was diluted with 100 mL of Water. The pH value of thesolution was adjusted to 7 with HCl (2 mol/L). The resulting solutionwas extracted with 3×30 ml of EtOAc dried over anhydrous sodium sulfateand concentrated under vacuum. The crude product was purified byTLC(PE:EA=1:2). This resulted in 410 mg (33.96%) of 74-1 as a whitesolid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-methoxy-2-oxoethoxy)acetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (75-1). Into a 25-mLround-bottom flask, was placed 74-1 (110 mg, 0.16 mmol, 1 equiv.), DCM(6 mL, 94.38 mmol, 579.919 equiv.), MeOH (2 mL, 49.40 mmol, 303.524equiv.). This was followed by the addition of(trimethylsilyl)diazomethane (0.12 mL, 0.11 mmol, 1.5 equiv., 2M in THF)dropwise with stirring. The resulting solution was stirred for 12 hr atroom temperature. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:1). This resulted in 110 mg (97.97%) of 75-1 as a solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-Methoxy-2-oxoethoxy)acetamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (75-2). Into a 25-mLround-bottom flask purged and maintained with an inert atmosphere of H₂,was placed 75-1 (110 mg, 0.16 mmol, 1 equiv.), MeOH (2 mL, 0.06 mmol,0.391 equiv.), Pd/C (50 mg, 0.47 mmol, 2.947 equiv.). The resultingsolution was stirred for 2 hr at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase,water (0.05% TFA) and ACN (5% Phase B up to 56% in 1 min, up to 70% in 7min); Detector, UV. This resulted in 36.6 mg (38.27%) of 75-2 as a whitesolid. MS (ES, m/z): [M+H]⁺=600.40; ¹H NMR (300 MHz, DMSO-d6) δ 12.18(s, 1H), 7.22 (d, J=9.7 Hz, 1H), 5.41 (s, 1H), 4.23 (s, 2H), 3.98 (s,2H), 3.67 (s, 3H), 3.56 (t, J=11.2 Hz, 1H), 2.63 (d, J=13.4 Hz, 1H),2.42 (s, 1H), 2.13-2.01 (m, 2H), 1.86-1.60 (m, 6H), 1.54 (d, J=14.9 Hz,1H), 1.36 (d, J=14.0 Hz, 9H), 1.21-0.85 (m, 13H), 0.83-0.72 (m, 9H).

Example 47(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-Methoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (76-4)

Synthesis of Benzhydryl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(prop-2-yn-1-yloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (76-2). Into a 25-mL round-bottomflask, was placed 76-1 (prepared as described in Bioorg. Med. Chem.2010, 18, 433-454) (1.674 g, 2.63 mmol, 1.00 equiv), THE (2.15 mL),NaHMDS (2.63 mL, 2.00 equiv), 3-bromoprop-1-yne (0.45 mL, 2.00 equiv),TBAI (486 mg, 1.32 mmol, 0.50 equiv). The resulting solution was stirredfor overnight at room temperature. The resulting solution was dilutedwith 30 mL of water. The resulting solution was extracted with 2×50 mLof DCM and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:10). This resulted in1.395 g (79%) of 76-2 as a light yellow solid.

Synthesis of Benzhydryl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-methoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(76-3). Into a 50-mL round-bottom flask, was placed 76-2 (100 mg, 0.15mmol, 1.00 equiv), t-BuOH—H₂O(3:1) 8 mL, methyl 2-azidoacetate (0.043mL, 3.00 equiv), Na ascorbate (17.6 mg, 0.09 mmol, 0.60 equiv),CuSO₄·5H₂O (11.1 mg, 0.04 mmol, 0.30 equiv). To the above N₂ (g) wasintroduced in. The resulting solution was stirred for 3 h at 40° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with DCM/MeOH (10:1). This resulted in 110 mg(94%) of 76-3 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-Methoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (76-4).Into a 50-mL round-bottom flask, was placed 76-3 (106 mg, 0.13 mmol,1.00 equiv), EtOAc (15 mL), palladium on carbon (50 mg). To the abovehydrogen was introduced in. The resulting solution was stirred forovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was dissolved in of. The crude product (8 mL)was purified by Prep-HPLC with the following conditions: Column, XBridgePrep OBD C18 Column, 19*250 mm, Sum; mobile phase, water (0.05% TFA) andACN (64.0% ACN up to 80.0% in 9 min); Detector, UV 254 nm. This resultedin 35.4 mg (42%) of 76-4 as a white solid. MS (ES, m/z): [M+H]⁺=624.55;¹H NMR (400 MHz, DMSO-d₆, ppm): δ 0.70-0.85 (d, 7H), 0.86 (s, 3H),0.89-1.01 (m, 2H), 1.02-1.10 (m, 6H), 1.10-1.19 (m, 4H), 1.21-1.56 (m,1OH), 1.62-1.81 (m, 6H), 2.05-2.09 (m, 2H), 2.33 (s, 1H), 2.66 (d,J=13.6 Hz, 1H), 2.96 (dd, J=11.6, 4.4 Hz, 1H), 3.71 (s, 3H), 4.45 (d,J=12.4 Hz, 1H), 4.67 (d, J=12.4 Hz, 1H), 5.40 (d, J=7.2 Hz, 3H), 8.07(s, 1H), 12.21 (br s, 1H).

Example 48(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-Methoxy-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (79-2)

Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-benzhydryl10-(2-methoxy-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (79-1). A mixture of 78-1 (50mg 0.072 mmol), iodomethane (170 mg, 1.2 mmol) and K₂CO₃ (30 mg, 0.22mmol) in DMF (0.30 mL) was stirred and heated at 60° C. After 3 hours,EtOAc (20 mL) was added and the mixture was washed with water (5 mL),10% Na₂S₂O₃ (3 mL) and water (5 mL). The organic layer was dried(Na₂SO₄), concentrated and purified by flash chromatography (4 g SiO₂,0-20% EtOAc/hexane) to give the title compound (32.7 mg).

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (79-2). A mixture of 79-1 (32.7 mg, 0.046mmol) and 10% Pd/C (˜50% water, 18 mg wet weight) in MeOH (2.0 mL) andTHE (1.0 mL) was stirred under 1 atm of H₂. After 2 hours, the mixturewas filtered, concentrated and purified by flash chromatography (4 gSiO₂, 20-60% EtOAc/hexane) to give the title compound (24 mg). MS (ES,m/z): 543.3 [M+H]⁺; ¹H-NMR (CDCl₃) δ 5.71 (s, 1H), 4.17 (d, J=16.2 Hz,1H), 4.08 (d, J=16.2 Hz, 1H), 3.74 (s, 3H), 2.94 (dd, J=11.8 Hz, J=4.5Hz, 1H), 2.82 (dt, J=13.5 Hz, J=3.5 Hz, 1H), 2.34 (s, 1H), 2.18 (dd,J=13.3 Hz, J=3.5 Hz, 1H), 1.34 (s, 3H), 1.23 (s, 3h), 1.15 (s, 3H), 1.13(s, 3H), 1.07 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.69 (d, J=10.2 Hz,1H).

Example 49(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-Dimethoxy-1,3-dioxopropan-2-yl)oxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (80-3)

Synthesis of Dimethyl2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)oxy)malonate (80-2). Into a 100-mL3-necked round-bottom flask, was placed 80-1 ((prepared as described inBioorg. Med. Chem. 2012, 22, 3473-3479) (680 mg, 1.21 mmol, 1.00 equiv),toluene (20 mL), Rh₂(OAc)₄ (8 mg). This was followed by the addition ofa solution of 1,1-bis(methoxycarbonyl)diaziridin-1-ium (383 mg, 2.38mmol, 1.96 equiv) in toluene (4 mL) dropwise with stirring at 90° C. in1 hr. The resulting solution was stirred for 2 h at 90° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:3). This resulted in 700mg (84%) of 80-2 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-Dimethoxy-1,3-dioxopropan-2-yl)oxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (80-3). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂(1 atm), was placed 80-2 (700 mg, 1.01 mmol, 1.00 equiv), MeOH (10 mL),palladium on carbon (70 mg). The resulting solution was stirred for 3 hat room temperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XBridge Prep C18 OBD Column,19*150 mm, Sum; mobile phase, water (0.05% TFA) and ACN (76.0% ACN up to81.0% in 10 min); Detector, UV 254 nm. This resulted in 59.7 mg (10%) of80-3 as a white solid. MS (ES, m/z): [M+H]⁺=601.40; ¹H-NMR (400 MHz,MeOH-d₄, ppm): δ 0.78-0.86 (m, 1H), 0.88-0.98 (m, 6H), 0.99-1.07 (m,4H), 1.16-1.19 (m, 9H), 1.19-1.26 (m, 1H), 1.40-1.52 (m, 9H), 1.63-1.87(m, 7H), 1.91-1.96 (m, 1H), 2.16-2.24 (m, 2H), 2.46 (s, 1H), 2.77 (d,J=13.2 Hz, 1H), 3.08-3.12 (m, 1H), 3.78 (s, 6H), 4.86 (s, 1H), 5.61 (s,1H).

Example 50(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(Ethoxycarbonyl)piperidin-1-yl)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (88-2)

Synthesis of Benzhydryl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(allyloxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (82-1). Into a 250-mL round-bottom flask, wasplaced 76-1 (2.3 g, 3.61 mmol, 1.00 equiv), THE (5 mL), NaHMDS (2M inTHF) (3.61 mL, 2.00 equiv), 3-bromoprop-1-ene (870 mg, 7.19 mmol, 2.00equiv), TBAI (667 mg, 0.50 equiv). The resulting solution was stirredfor 5 h at 50° C. The resulting solution was diluted with 100 mL of EA.The resulting mixture was washed with 2×50 mL of H₂O. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:50). This resulted in 1.37 g (56%) of 82-1 as a white solid.

Synthesis of benzhydryl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(oxiran-2-ylmethoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (82-2). Into a 250-mL round-bottomflask, was placed a solution of 82-1 (1.37 g, 2.02 mmol, 1.00 equiv) inDCM (10 mL). This was followed by the addition of a solution of m-CPBA(1.75 g, 10.14 mmol, 5.00 equiv) in DCM (10 mL) dropwise with stirring.The resulting solution was stirred overnight at 30° C. The reaction wasthen quenched by the addition of 15 mL of 3M sodium hydroxide. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 3×150 mL of EtOAc and the organic layers combined.The resulting mixture was washed with 1×100 mL of waterand 1×100 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM/EtOAc (50:1). The collected fractions were combined andconcentrated under vacuum. This resulted in 1.1 g (78%) of 82-2 as awhite solid.

Synthesis of ethyl1-(3-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)oxy)-2-hydroxypropyl)piperidine-4-carboxylate(88-1). A solution of 82-2 (430 mg, 0.62 mmol) and isonipecotate (340mg) in THE (6.0 mL) and water (1.0 mL) was heated at 70° C. After 2.5hours the reaction mixture was concentrated under vacuum and useddirectly in the next step. A mixture of 88-1 (0.62 mmol) and wet 10%Pd/C (˜50% water, 100 mg wet weight) in THE (4.0 mL) and MeOH (4.0 mL)was stirred under one atm of H₂. After 2 hours, the final product waspurified by flash chromatography (4 g SiO₂, 0-15% MeOH/DCM) to give thetitle compound. MS (ES, m/z): 684.2 [M+H]⁺; ¹H-NMR (CDCl₃) δ 5.68 (s,1H), 4.14 (quar, J=7.0 Hz, 2H), 3.95 (m, 1H), 3.67-3.55 (m, 1H),3.36-3.25 (m, 1H), 3.08-2.92 (m, 2H), 2.33 (s, 1H), 1.36 (s, 3H), 1.25(t, J=7.0 Hz, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H), 0.98 (s,3H), 0.82 (s, 3H), 0.79 (s, 3H).

Example 51(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((Carboxymethyl)amino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (94-2)

Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-Benzhydryl10-(3-(2-(benzyloxy)-2-oxoethylamino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(94-1). A mixture of 82-2 (30 mg 0.043 mmol), benzyl glycinate (14 mg,0.086 mmol) and calcium trifluoromethylsulfonate (5 mg, 0.014 mmol) inacetonitrile (0.5 mL) was heated at 80° C. for 2 hours and then cooledto RT overnight. The reaction mixture was then heated at 80° C. for 2hours, added to 5% Na₂CO₃ (5 mL) and extracted with DCM (4×10 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated to give the crudeintermediate (57 mg).

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((Carboxymethyl)amino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (94-2). A mixtureof crude 94-1 from step 1 (57 mg) and wet 10% Pd/C (50% water, 10 mg wetweight) in MeOH (1 mL) and THE (1 mL) was stirred under 1 atm of H₂ for2 days. The mixture was filtered, concentrated and purified bypreparative HPLC to give a TFA salt of the title compound (2.5 mg) as awhite powder. MS (ES, m/z): 602.2 [M+H]⁺

Example 52(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((Carboxymethyl)(methyl)amino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (95-2)

Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-Benzhydryl10-(3-((2-tert-butoxy-2-oxoethyl)(methyl)amino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(95-1). A solution of 82-2 (40 mg, 0.058 mmol) and tert-butyl sarcosine(46 mg, 0.32 mmol) in THF (0.50 mL) and water (0.10 mL) was heated at65° C. for 5 hours. The reaction was concentrated to dryness andpurified by flash chromatography (4 g SiO₂, 0-5% MeOH/DCM) to give thetitle compound (47 mg).

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-((Carboxymethyl)(methyl)amino)-2-hydroxypropoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (95-2).Trifluoroacetic acid (0.30 mL) was added slowly to a solution of 95-1(47 mg, 0.056 mmol) in DCM (0.30 mL). After 4.5 hours, Heptane (10 mL)was added and the mixture concentrated to dryness. The crude product 4byLCMS showed the product contained ˜10% of the lactone. MS (ES, m/z):616.3 [M+H]⁺; ¹H-NMR (DMSO, d₆) δ 5.41 (s, 1H), 4.01 (br s, 2H), 3.57(dd, J=10.0 Hz, J=4.7 Hz, 0.5H), 3.45 (dd, J=9.6 Hz, J=6.1 Hz, 0.5H),3.30-3.05 (m, 2H), 2.84 (s, 3H), 2.80 (m, 1H), 2.66 (d, J=13.3 Hz, 1H),2.34 (s, 1H), 2.13-2.04 (m, 2H), 1.35 (s, 3H), 1.10 (s, 3H), 1.04 (s,6H), 0.95 (s, 3H), 0.76 (s, 1H), 0.73 (s, 3H).

Example 531-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-Carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oicacid (110-3)

Synthesis of tert-Butyl1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate(110-1). Into a 250-mL round-bottom flask, was placed 1-7 (515 mg, 0.85mmol, 1.00 equiv), DCM (50 mL), tert-butyl3-2-[2-(2-aminoethoxy)ethoxy]ethoxypropanoate (589 mg, 2.12 mmol, 2.50equiv), TEA (0.885 mL, 7.50 equiv). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:1). This resulted in 533 mg (74%) of 110-1 as alight yellow solid.

Synthesis of1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oicacid (110-2). Into a 250-mL round-bottom flask, was placed 110-1 (533mg, 0.63 mmol, 1.00 equiv), DCM (15 mL), trifluoroacetic acid (15 mL).The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The resulting mixturewas washed with 2×10 mL of diethyl ether. This resulted in 497 mg (100%)of 110-2 as light yellow crude oil.

Synthesis of1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-Carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oicacid (110-3). Into a 50-mL round-bottom flask purged and maintained withan inert atmosphere of H₂ (1 atm), was placed 110-2 (150 mg, 1 equiv),THE (10 mL), Pd/C (15 mg). The resulting solution was stirred overnightat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (42% ACNup to 60% in 8 min); Detector, UV 254 nm. This resulted in 65.8 mg(49.5%) of 110-3 as a white solid. MS (ES, m/z): [M+H]⁺=702.40; ¹H NMR(400 MHz, MeOH-d₄, ppm): δ 0.86 (s, 3H), 0.88 (s, 1H), 0.94 (s, 3H),0.99-1.11 (m, 5H), 1.17 (s, 3H), 1.19 (s, 3H), 1.21 (s, 3H), 1.21 (d,J=7.3 Hz, 1H), 1.35-1.55 (m, 9H), 1.61-2.08 (m, 8H), 2.10-2.29 (m, 2H),2.52 (s, 1H), 2.57 (t, J=6.4 Hz, 2H), 2.80 (d, J=13.6 Hz, 1H), 3.34-3.47(m, 2H), 3.55 (t, J=5.4 Hz, 2H), 3.60-3.69 (m, 8H), 3.76 (t, J=6.4 Hz,2H), 5.60 (s, 1H).

Example 54(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((3-oxo-2,6,9,12-tetraoxatetradecan-14-yl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (113-2)

Synthesis of Methyl1-((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate(113-1) Into a 250-mL round-bottom flask, was placed 110-2 (508 mg, 0.64mmol, 1.00 equiv), DCM (15 mL), MeOH (15 mL). This was followed by theaddition of TMSCHN₂ in n-hexane (2M) (0.96 mL, 3.00 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 517 mg (100%) of 113-1 as a yellow crude solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((3-oxo-2,6,9,12-tetraoxatetradecan-14-yl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (113-2). Intoa 250-mL round-bottom flask purged and maintained with an inertatmosphere of H₂ (1 atm), was placed 113-1 (517 mg, 1 equiv), MeOH (10mg), THF (10 mg), Pd/C (52 mg). The resulting solution was stirredovernight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, Sum, 19*150 mm; mobile phase, water (0.05% TFA)and ACN (48% Phase B up to 68% in 8 min); Detector, UV 254 nm. Thisresulted in 29.6 mg (6.45%) of 113-2 as a white solid. MS (ES, m/z):[M+H]⁺=716.45; ¹H NMR (400 MHz, MeOH-d₄, ppm): δ 0.86 (s, 3H), 0.88 (s,1H), 0.94 (s, 3H), 0.97-1.11 (m, 5H), 1.17 (s, 3H), 1.19 (s, 3H), 1.21(s, 3H), 1.28 (d, J=13.8 Hz, 1H), 1.34-1.55 (m, 9H), 1.63-1.81 (m, 3H),1.82-2.09 (m, 5H), 2.10-2.25 (m, 2H), 2.49 (s, 1H), 2.58 (t, J=6.2 Hz,2H), 2.78 (d, J=13.6 Hz, 1H), 3.32-3.35 (m, 1H), 3.36-3.44 (m, 1H), 3.53(t, J=5.2 Hz, 2H), 3.60 (s, 8H), 3.67 (s, 3H), 3.74 (t, J=6.2 Hz, 2H),5.58 (s, 1H).

Example 55(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatetradecane)sulfonamido)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (114-2)

Synthesis of3-(N-((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)sulfamoyl)propanoicacid (112-1). 72-1 (200 mg, 0.282 mmol) and lithium hydroxidemonohydrate (13.0 mg, 0.309 mmol) in THF and water were stirred for 4 hrat room temperature. The reaction was acidified with 6N HCl, partiallyevaporated under vacuum, diluted with water and extracted with DCM. Theextract was dried (Na₂SO₄) and evaporated to give 0.195 g (99%) 112-1 asa white solid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatetradecane)sulfonamido)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(114-1). Into a 100-mL round-bottom flask, was placed 112-1 (200 mg,0.29 mmol, 1 equiv), DMF (20 mL),2-[2-(2-methoxyethoxy)ethoxy]ethan-1-ol (190 mg, 1.16 mmol, 4.03 equiv),EDCI (140 mg, 0.73 mmol, 2.54 equiv), DMAP (210 mg, 1.72 mmol, 5.98equiv). The resulting solution was stirred overnight at 65° C. Theresulting solution was extracted with 200 mL of EtOAc. The resultingmixture was washed with 1×200 mL of brine. The mixture was dried overanhydrous sodium sulfate. The solids were filtered out. This resulted in100 mg (41.3%) of 114-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatetradecane)sulfonamido)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (114-2). Into a100-mL round-bottom flask, was placed 114-1 (100 mg, 0.12 mmol, 1equiv), THE (5 mL), EA (10 mL), Pd/C (20 mg, 0.19 mmol, 1.583 equiv). Tothe above H₂ (g, 1 atm) was introduced in. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Theresulting mixture was concentrated. The crude product was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (54%Phase B up to 67% in 8 min); Detector, UV 254 nm. This resulted in 7.9mg (8.9%) of 114-2 as a white solid. MS (ES, m/z): [M+H]⁺=752.35; ¹H NMR(400 MHz, MeOH-d₄, ppm): δ 0.78-0.94 (m, 7H), 0.95-1.24 (m, 15H),1.53-2.07 (m, 9H), 2.08-2.28 (m, 2H), 2.52 (s, 1H), 2.70-2.90 (m, 3H),2.97-3.11 (m, 2H), 3.35-3.45 (m, 5H), 3.52-3.62 (m, 3H), 3.63-3.72 (m,9H), 3.73-3.86 (m, 2H), 4.20-4.32 (m, 2H), 5.60 (s, 1H), 7.25 (d, J=12.8Hz, 1H).

Example 56(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(4-oxo-2,8,11,14-tetraoxa-5-azapentadecanoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,2,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (115-2)

Synthesis of 2-Benzyl 10-(12-oxo-2,5,8-trioxa-11-azatridecan-13-yl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (115-1). Into a200-mL round-bottom flask, was placed 13-2 (200 mg, 0.31 mmol, 1 equiv),DCM (10 mL, 0.12 mmol), DMAP (18 mg, 0.15 mmol, 0.477 equiv), EDCI (116mg, 0.61 mmol, 1.957 equiv), 1-[2-(2-aminoethoxy)ethoxy]-2-methoxyethane(59 mg, 0.36 mmol, 1.169 equiv). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentrated.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:1). This resulted in 200 mg (81.67%) 115-1 as a white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-(4-oxo-2,8,11,14-tetraoxa-5-azapentadecanoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (115-2). Into a 100-mLround-bottom flask purged and maintained with an inert atmosphere of H₂(1 atm), was placed 115-1 (200 mg, 0.25 mmol, 1 equiv), MeOH (10 mL,0.31 mmol, 1.236 equiv), Pd/C (20 mg, 0.19 mmol, 0.744 equiv). Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated. The crude product was purified byPrep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Shield RP18 OBDColumn, Sum, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (53%Phase B up to 68% in 8 min); Detector, UV 254 nm. This resulted in 39.3mg (22.17%) of 115-2 as a white solid. MS (ES, m/z): [M+H]⁺=702.50;¹NMR-PH-RDX-013-585-0: (400 MHz, MeOH-d₄, ppm): δ 0.81-0.94 (m, 7H),1.09-1.18 (m, 5H), 1.19-1.21 (m, 9H), 1.22-1.26 (m, 1H), 1.43-1.74 (m,12H), 1.76-2.01 (m, 4H), 2.15-2.24 (m, 2H), 2.38 (d, J=12.8 Hz, 1H),2.53 (s, 1H), 2.81 (d, J=13.2 Hz, 1H), 3.33-3.34 (m, 3H), 3.35-3.43 (m,2H), 3.56-3.67 (m, 10H), 4.70 (AB q, J=11.6 Hz, 2H), 5.60 (s, 1H).

Example 57(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-Hydroxy-9-(methoxycarbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (123-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(acetoxyimino)-9-(acetoxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(120-2). Into a 250-mL round-bottom flask, was placed 120-1 (preparedfrom 109-1 as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.0 g,1.7 mmol, 1.00 equiv), AcOH (100 mL), Na₂PdCl₄ (0.76 g, 2.04 mmol, 1.20equiv), NaOAc (0.21 g, 1.36 mmol, 0.80 equiv). The mixture was stirredat room temperature (˜15-20° C.) for 72 h. It was then poured onto ice.After a few hours, the precipitate was collected by filtration, themixture was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated under vacuum. ThenDCM (120 mL), acetic anhydride (0.435 g, 3.24 mmol, 1.80 equiv), TEA(0.364 g, 2.72 mmol, 1.60 equiv) and DMAP (6 mg, 0.02 equiv) were added.The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was washed with 1×300 mL of water. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. Pyridine (0.6 mL), THF(100 mL) was added, and the solution was stirred at room temperature for15 min. After cooled to −78° C., Pb(OAc)₄ (4.9 g, 8.5 mmol, 5 equiv)dissolved in AcOH (100 mL) was added slowly. After complete addition,the mixture was allowed to warm to room temperature and was then stirredat room temperature for 16 h. A solution of NaBH₄ (60 mg) in 1 N aqueousNaOH solution (50 mL) was added, and stirring was continued for 10 min.The mixture was filtered through celite. The resulting solution wasextracted with 300 mL of DCM and the organic layers combined. Theresulting mixture was washed with 3×300 mL of sat. NaHCO₃ and 2×300 mLof brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 1.03 g (88%, crude) of 120-2 as a light yellowsolid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(hydroxyimino)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(120-3). Into a 250-mL round-bottom flask, was placed 120-2 (1.03 g,1.53 mmol, 1.00 equiv), MeOH (120 mL), sodium carbonate (820 mg, 7.74mmol, 5.00 equiv). The resulting solution was stirred for 16 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was extracted with 200 mL of DCM and the organiclayers combined. The resulting mixture was washed with 2×200 mL ofsodium bicarbonate and 1×200 mL of brine. The solid was dried in an ovenunder reduced pressure. The solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 1.1 g (crude) of120-3 as a yellow solid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(120-4). Into a 250-mL round-bottom flask, was placed NH₄OAc (3.88 g,27.00 equiv), water (80 mL), TiCl₃ (4 mL). This was followed by theaddition of a solution of 120-3 (1.1 g, 1.87 mmol, 1.00 equiv) in THE(70 mL) dropwise with stirring in 15 min. To this was added THE (70 mL).The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 200 mL of DCM and the organic layers combined. Theresulting mixture was washed with 1×200 mL of sodium bicarbonate and1×200 mL of brine. The mixture was dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:1). This resulted in 190 mg (18%) of 120-4 as awhite solid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(121-1). Into a 100-mL round-bottom flask, was placed 120-4 (150 mg,0.26 mmol, 1.00 equiv), MeOH (20 mL), NaBH₄ (40 mg, 1.06 mmol, 4.00equiv). The resulting solution was stirred for 1 h at room temperature.The reaction was then quenched by the addition of 5 mL of water. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 100 mL of DCM and the organic layers combined. Theresulting mixture was washed with x mL of and 1×100 mL of brine. Themixture was dried over anhydrous sodium sulfate. This resulted in 140 mg(93%) of 121-1 as a white solid.

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-formyl-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate(122-1). Into a 100-mL round-bottom flask, was placed 121-1 (300 mg,0.52 mmol, 1.00 equiv), DCM (25 mL), PH 8.6 buffer (5 mL), TEMPO (240mg, 1.54 mmol, 3.00 equiv), TBACl (0.36 g, 2.50 equiv), NCS (280 mg,2.10 mmol, 4.00 equiv). The resulting solution was stirred overnight at40° C. The resulting solution was extracted with 200 mL of DCM and theorganic layers combined. The resulting mixture was washed with 1×200 mLof water and 1×200 mL of brine. The mixture was dried over anhydroussodium sulfate. This resulted in 0.4 g (134%, crude) of 122-1 as ayellow semi-solid.

Synthesis of(3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((Benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylicacid (122-2). Into a 250-mL round-bottom flask, was placed 122-1 (400mg, 0.70 mmol, 1.00 equiv), tert-butanol (12 mL), water (6 mL),2-methylbut-2-ene (2 mL), NaH₂PO₄ (0.5 g, 6.00 equiv), NaClO₂ (0.38 g,6.00 equiv). The resulting solution was stirred for 30 min at −2° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 200 mL of DCM and the organic layers combined. Theresulting mixture was washed with 1×200 mL of brine. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. This resulted in 0.758g (184%, crude) of 122-2 as a yellow semi-solid.

Synthesis of 2-Benzyl 9-methyl(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate(123-1). Into a 100-mL round-bottom flask, was placed 122-2 (500 mg,0.85 mmol, 1.00 equiv.), DCM (10 mL), MeOH (10 mL), TMSCH₂N₂ (5 mL,10.00 equiv). The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was extracted with 200 mL of DCM and the organiclayers combined. The resulting mixture was washed with 1×200 mL of waterand 1×200 mL of brine. The mixture was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 0.6 g (117%, crude) of 123-1as a yellow semi-solid.

Synthesis of(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-Hydroxy-9-(methoxycarbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylicacid (123-2). Into a 100-mL round-bottom flask, was placed 123-1 (600mg, 0.99 mmol, 1.00 equiv), EtOAc (20 mL), palladium on carbon (0.12 g,0.20 equiv). To the above hydrogen (1 atm) was introduced in. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, Sum, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (48.0% ACN up to 62.0% in 8min); Detector, UV 254 nm. This resulted in 29.7 mg (6%) of 123-2 as awhite solid. MS (ES, m/z): [M+H]⁺=515.30; ¹H NMR (400 MHz, MeOH-d₄,ppm): δ 0.75 (s, 3H), 0.88-1.01 (m, 2H), 1.02-1.18 (m, 14H), 1.28-1.39(m, 7H), 1.43 (d, J=11.6 Hz, 1H), 1.48-1.59 (m, 2H), 1.60-1.70 (m, 3H),1.71-1.92 (m, 3H), 2.01-2.22 (m, 2H), 2.53 (s, 1H), 2.79 (dt, J=13.6,3.5 Hz, 1H), 3.64 (s, 3H), 3.87 (dd, J=11.8, 4.7 Hz, 1H), 5.54 (s, 1H).

Example 58(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-oxo-2-(((R)-quinuclidin-3-yl)oxy)ethyl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (124-2)

Synthesis of Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2-oxo-2-(((R)-quinuclidin-3-yl)oxy)ethyl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (124-1).Into a 50-mL round-bottom flask, was placed 29-1 (100 mg, 0.15 mmol,1.00 equiv), toluene (10 mL), (3R)-1-azabicyclo[2.2.2]octan-3-ol (60 mg,0.47 mmol, 3.00 equiv), titanium(IV) isopropoxide (0.14 mL, 3.00 equiv).The resulting solution was stirred overnight at 110° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with DCM/MeOH (5:1). This resulted in 20 mg (17%) of124-1 as an off-white solid.

Synthesis of(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-Heptamethyl-13-oxo-10-((2-oxo-2-(((R)-quinuclidin-3-yl)oxy)ethyl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (124-2). Into a100-mL round-bottom flask, was placed 124-1 (45 mg, 0.06 mmol, 1.00equiv), MeOH (20 mL), palladium on carbon (10 mg). To the above hydrogen(1 atm) was introduced in. The resulting solution was stirred for 1 h atroom temperature. The solids were filtered out. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, Sum, 19*150 mm; mobile phase, water (0.05% TFA)and ACN (30.0% ACN up to 56.0% in 8 min); Detector, UV 254/220 nm. Thisresulted in 11.6 mg (29%) of 124-2 as a white solid. MS (ES, m/z):[M+H]⁺=665.45; ¹H NMR (300 MHz, MeOH-d₄, ppm): δ 0.84 (s, 3H), 0.87 (s,1H), 0.92 (s, 3H), 0.96-1.01 (m, 2H), 1.07 (s, 3H), 1.16 (s, 3H), 1.17(s, 3H), 1.19 (s, 3H) 1.23-1.29 (m, 1H), 1.40-1.53 (m, 8H), 1.63-1.76(m, 3H), 1.79-2.32 (m, 11H), 2.38 (s, 1H), 2.50 (s, 1H), 2.80 (dt,J=13.5 Hz, 3.3 Hz, 1H), 3.33-3.40 (m, 6H), 3.70-3.79 (m, 1H), 3.88 (d,J=17.3 Hz, 1H), 3.99 (d, J=17.3 Hz, 1H), 5.10-5.17 (m, 1H), 5.58 (s,1H).

Example 59 HSD2 Activity

Human descending colon epithelial stem cells were cultured as 3Dorganoids in accordance with Sato et al. Gastroenterology. 2011November; 141(5):1762-72. Organoids were dissociated using TrypLEExpress (life technologies) and plated on 96-well transwells (corning)in supplemented basal media (SBM—advanced DMEM/F12 containing 10 mMHEPES, 1:100 Glutamax, 1:100 penicillin/streptomycin, 1:100 N2, 1:50B27, 1 mM N-acetylcysteine, 10 nM [Leu15]-gastrin I) containing 100ng/mL Wnt3A (W), 50 ng/mL EGF (E), 100 ng/mL Noggin (N), 500 ng/mLRSpondinl (R), 500 nM A83-01 (A) and 2.5 uM thiazovivin (T). Cultureswere differentiated using SBM containing ENRA and 30 nM aldosterone onday 3, and cultures were used for assay on day 6 or 7. Compounds werediluted in DMSO and serial dilutions prepared by titrating in DMSO.Compounds were then diluted into DMEM/F12. Transwell plates containingdescending colon cultures were washed twice with DMEM/F12 and compoundwas added to the apical compartment. Cells were incubated with testcompound for 30 minutes at 37° C., 5% CO₂ to equilibrate across the cellmembrane. A second compound plate was prepared in which the seriallydiluted compounds in DMSO were diluted into DMEM/F12 containing 40 nMcortisol. Following the 30 minute pre-incubation step, the apical mediawas aspirated and compounds diluted in DMEM/F12 with 40 nM cortisol wereadded to the apical side of the transwell. The plate was then incubatedfor four hours at 37° C., 5% CO₂. Cortisol levels were measured using acortisol HTRF assay kit as described by the manufacturer (Cisbio).Concentration-response curves were then plotted and IC₅₀ values weredetermined using least squares non-linear regression.

Example 60 Stability Assays

Sample were analyzed on an Agilent 6410 triple-quadrapole LC-MS systemconsisting of an Agilent 1260 LC with a Phenomenex Gemini 5 μm column(NX-C18, 110 A, 30×2 mm) and the mass spectrometer with an electrosprayinterface running under a positive ionization mode. Mobile phases were0.1% formic acid in water and 0.1% formic acid in acetonitrile.

Plasma Stability—Plasma from pooled male rat or human (purchased fromBioreclamationIVT, LLC) were pre-warmed to 37° C. Compounds were thenadded to the plasma samples to make a final concentration of 1 μM andvortexed. Duplicate samples of 100 μL each were taken out at Time 0, 10,20, 30 and 60 min for extraction and analysis. Extraction and analysisof parent drug were by addition of 300 μL of acetonitrile containing 500ng/mL of internal standard (labetalol), vortexing, and centrifugation.150 μL of the supernatant was added to 100 μL of deionized water and 10μL injected onto LC/MS.

Liver S9 Homogenate Stability—Liver S9 homogenate from pooled male rator human (purchased from Xenotech, LLC, 20 mg protein/mL) was dilutedwith 0.05M KH₂PO₄, pH 7.4 buffer to make 0.8 mg protein/mL andpre-warmed to 37° C. Compounds were then added to the homogenate samplesto make a final concentration of 1 μM and vortexed. Duplicate samples of100 μL each were taken out at Time 0, 5, 15, 30 and 120 min forextraction and analysis. Extraction and analysis of parent drug were byaddition of 300 μL of acetonitrile containing 100 ng/mL of internalstandard (labetalol), vortexing, and centrifugation. 150 μL of thesupernatant was added to 100 μL of deionized water and 10 μL injectedonto LC/MS.

Liver Microsomal Stability—Liver microsome from pooled male rat or human(purchased from Xenotech, LLC, 20 mg protein/mL) was diluted with 0.05MKH₂PO₄, pH 7.4 buffer containing 5 mM MgCl₂ to make 0.5 mg protein/mLand pre-warmed to 37° C. Compounds were then added to the homogenatesamples to make a final concentration of 1 μM and vortexed. NADPH in0.05M KH₂PO₄, pH 7.4 buffer was then added to make the finalconcentration of 2 mM to start the reaction. Duplicate samples of 100 μLeach were taken out at Time 0, 3, 6, 10, 15, 20 and 30 min forextraction and analysis. Extraction and analysis of parent drug were byaddition of 100 μL of acetonitrile containing 100 ng/mL of internalstandard (labetalol), vortexing, and centrifugation. 10 μL of thesupernatant was injected onto LC/MS. An incubation without the NADPHaddition was used as a control for the experiment.

Cecal-Colonic Extract Stability—Female rats (non-fasted) were euthanizedand the cecum and colon taken out and weighed. The intestinal contentsin the cecum and colon were flushed out with 20 mL deionized water andthe tissues re-weighed. Deionized water was added to the cecal-coloniccontent mixture to make a 10×w/v dilution. The mixture was thenhomogenized by a Polytron homogenizer for 2 minutes and centrifuged at5000 rpm in a Beckman Allegra 25r centrifuge for 10 minutes. Thesupernatant was taken out and warmed to 37° C. in a shaking water. 1.5mL Aliquots were then added compounds to make a final concentration of 1μM and vortexed. Duplicate samples of 100 μL each were taken out at Time0, 10, 20, 40, 60 and 180 min for extraction and analysis. Extractionand analysis of parent drug were by addition of 300 μL of acetonitrilecontaining 500 ng/mL of internal standard (labetalol), vortexing, andcentrifugation. 150 μL of the supernatant was added to 100 μL ofdeionized water and 10 μL injected onto LC/MS.

1. A compound of formula I or a salt thereof:

wherein, X is a bond, —O—, —C(O)—, —N(R_(x))—, —C(O)N(R_(x))—,—N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or —N(R_(x))—S(O)_(n)—; V is—C(O)O—, —C(O)N(R₅)—, —C(O)N(R₅)O—, —NH—C(O)—N(R₅)— or NH—S(O)_(n)—; Lis a bond, alkylene wherein one or more non-adjacent methylene groups ofsaid alkylene are replaced with —O—; divalent aryl or divalentheteroaryl; or L is alkylene-Y-alkylene wherein Y is O, NR_(x), S, SO,SO₂ or a divalent heterocycle; wherein said alkylene groups areoptionally substituted with OH, —C(O)O—R₁, alkyl or alkyl substitutedwith OH or —C(O)O—R₁; and wherein a carbon of said alkylene groups andR_(x) optionally together form a heterocycle; provided that when X isother than a bond, then L is other than a bond; R₁ is alkyl optionallysubstituted with halogen, OH, amino, oxo, carboxy, acyloxy,alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, acarbocycle optionally substituted with alkyl, haloalkyl, oxo, amino andhalogen and a heterocycle optionally substituted with alkyl, oxo, aminoand halogen; and a carbocycle or heterocycle optionally substituted withalkyl, haloalkyl, oxo, amino and halogen; wherein one or morenon-adjacent methylene groups in any of the foregoing alkyl groups isreplaced with O; R₂ is H or R₁; R₃ is absent, Me; provided that when—X-L-C(O)O—R₁ depends from the carbon to which R₃ depends then R₃ isabsent; or R₃ is —Z-L-C(O)O—R₁ wherein Z is a bond, —O—, —N(R_(x))—,—C(O)N(R_(x))—, —N(R_(x))—C(O)—, —S(O)_(n)—N(R_(x))— or—N(R_(x))—S(O)_(n)—; and R₄ is absent, H or OH; provided that when—X-L-C(O)O—R₁ depends from the carbon to which R₄ depends then R₄ is Hor absent; R₅ is H or alkyl; R_(x) is H, —C(O)O—R₁, or alkyl optionallysubstituted with —C(O)O—R₁; and n is 1 or
 2. 2. The compound or salt ofclaim 1, having the structure of any one of Formula Ia-Ir:

or a salt thereof.
 3. The compound or salt of claim 1, wherein X is abond.
 4. The compound or salt of claim 1, wherein L is a bond.
 5. Thecompound or salt of claim 1, wherein X and L are both bonds.
 6. Thecompound or salt as claimed in claim 1, wherein R₂ is H.
 7. (canceled)8. The compound or salt as claimed in claim 1, wherein R₄ is H.
 9. Thecompound salt as claimed in claim 1, wherein X is absent and L is arylor heteroaryl.
 10. The compound or salt of claim 9, wherein L is phenyl,triazole or isoxazole.
 11. The compound or salt of claim 10 wherein R₃is hydrogen.
 12. The compound or salt as claimed in claim 11 wherein R₂and R₄ are each H.
 13. The compound or salt as claimed in claim 1,wherein X is O.
 14. The compound or salt as claimed in claim 1, whereinX is —C(O)—.
 15. The compound or salt as claimed in claim 1, wherein R₁is alkyl optionally substituted with halogen, OH, amino, oxo, carboxy,acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy,aminocarbonyl, a carbocycle optionally substituted with alkyl,haloalkyl, oxo, amino and halogen and a heterocycle optionallysubstituted with alkyl, oxo, amino and halogen; and heterocycleoptionally substituted with alkyl, haloalkyl, oxo, amino and halogen;wherein one or more non-adjacent methylene groups in said alkyl isreplaced with O.
 16. The compound or salt of claim 15, wherein R₁ ismethyl, propyl, hydroxyethyl, 2,2,2-trifluoroethyl,1,1-trifluoromethylethyl, 2-morpholinoethyl, 2-(1H-imidazol-1-yl)ethyl,2-(pyridin-2-yl)ethyl, —CH₂—C(O)OH, —CH₂—C(O)O-Me, —CH₂—C(O)NH₂,—CH₂—C(O)NMe₂, —CH₂—C(O)O-t-butyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (pivaloyloxy)methyl,((isopropoxycarbonyl)oxy)methyl, (S)-1-((isopropoxycarbonyl)oxy)ethyl,(R)-1-((isopropoxycarbonyl)oxy)ethyl, 2-morpholino-2-oxoethyl,2-(4-methylpiperazin-1-yl)-2-oxoethyl or (R)-quinuclidin-3-yl.
 17. Thecompound or salt of claim 15, wherein R₁ is methyl.
 18. A method ofinhibiting conversion of cortisol to cortisone by HSD2 comprisingcontacting HSD2 with a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 19. A method for treating a disease orcondition mediated by the conversion of cortisol to cortisone by HSD2,comprising administering to said mammal an effective amount of acompound as claimed in claim 1 or a pharmaceutically acceptable saltthereof.
 20. A method for promoting potassium ion secretion into thecolonic lumen of a mammal, comprising administering to said mammal aneffective amount of a compound as claimed in claim 1 or apharmaceutically acceptable salt thereof.
 21. A method for treatinghyperkalemia in a mammal, comprising administering to said mammal aneffective amount of a compound as claimed in claim 1 or apharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, diluent or excipient. 23-24. (canceled)